MONDO:0006541

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms that the cardinal feature of EB is blister formation triggered by minimal trauma due to mucocutaneous fragility.

[PMID:34036913] [INDIRECT EVIDENCE] [SUPPORT] a group of rare congenital genetic conditions that result in painful blistering of the skin and mucous membranes, which occur with minor trauma or friction --- Explanation: Confirms that blistering is triggered by minor trauma or friction in EB.


MONDO:0006541


MONDO:0006541

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma --- Explanation: Confirms that chronic wound complications including squamous cell carcinoma are major concerns in EB management.

[PMID:25279494] [INDIRECT EVIDENCE] [SUPPORT] a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection --- Explanation: Confirms that ulceration and impaired wound healing are significant complications requiring specialized management.


MONDO:0006541

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality --- Explanation: Confirms that EB has severe extracutaneous complications contributing to morbidity and mortality.

[PMID:20507631] [INDIRECT EVIDENCE] [SUPPORT] Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs --- Explanation: Confirms the broad range of secondary complications including internal organ involvement.


MAXO:0000950

[PMID:20507631] [SUPPORT] use of sophisticated wound care dressings --- Explanation: Confirms specialized wound care dressings as a key management strategy.

[PMID:34036913] [SUPPORT] involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications --- Explanation: Confirms wound care as a core pillar of EB management.

[PMID:25279494] [SUPPORT] global skin care including wound care --- Explanation: Confirms wound care as central to EB patient management.


MAXO:0000950

[PMID:34036913] [SUPPORT] involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications --- Explanation: Confirms pain control as a core component of EB management.

[PMID:25279494] [SUPPORT] management of itching and pain --- Explanation: Confirms pain and itch management as key aspects of EB care.


MAXO:0000088

[PMID:20507631] [SUPPORT] aggressive nutritional support --- Explanation: Confirms aggressive nutritional support as essential in EB management.

[PMID:34036913] [SUPPORT] involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications --- Explanation: Confirms nutritional support as a core management component.


MAXO:0000950

[PMID:34036913] [SUPPORT] involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications --- Explanation: Confirms infection control as a core pillar of EB management.

[PMID:25279494] [SUPPORT] a specific attention to the fragile skin is required in order to reduce pain, risk of trauma, ulceration and infection --- Explanation: Confirms infection prevention as key in EB wound management.


MAXO:0000079

[PMID:34036913] [SUPPORT] The diagnosis is suspected based on symptoms and confirmed by skin biopsy and definitive genetic testing --- Explanation: The role of genetic testing in diagnosis underscores the importance of genetic counseling for families.


MAXO:0001001

[PMID:36516090] [SUPPORT] Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo --- Explanation: Phase 3 NEJM trial demonstrating significant wound healing benefit of beremagene geperpavec over placebo in dystrophic EB.

[PMID:37432558] [SUPPORT] In May 2023, beremagene geperpavec received its first approval in the US for the treatment of wounds in patients --- Explanation: Confirms FDA approval in May 2023 as the first topical gene therapy for dystrophic EB.


MAXO:0000058

[PMID:36689495] [SUPPORT] Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB --- Explanation: Phase 3 EASE trial demonstrating Oleogel-S10 as the first therapy to show accelerated wound healing in EB.

[PMID:39748581] [SUPPORT] Filsuvez® (birch triterpenes) topical gel received approval in 2023 for the treatment of epidermolysis bullosa (EB) in pediatric patients (aged ≥6 months) and adults --- Explanation: Confirms FDA approval of Filsuvez for treatment of EB wounds in pediatric and adult patients.


MAXO:0000016

[PMID:40875177] [SUPPORT] Prademagene zamikeracel (ZEVASKYN™) is an autologous cell sheet-based gene therapy developed by Abeona Therapeutics Inc. for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa --- Explanation: Confirms FDA approval of prademagene zamikeracel as the first cell-based gene therapy for RDEB.

[PMID:31578311] [SUPPORT] Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001) --- Explanation: Phase 1/2a trial demonstrating significant wound healing with gene-corrected autologous cell therapy in RDEB patients.


HGNC.SYMBOL:KRT5

[PMID:32973163] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: Confirms that genes encoding structural proteins including keratins are causative of EB.


HGNC.SYMBOL:KRT14

[PMID:20301543] [SUPPORT] the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC --- Explanation: Supports KRT14 as a causative EB simplex gene in the clinical diagnostic framework.


HGNC.SYMBOL:COL7A1

[PMID:32973163] [SUPPORT] Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality --- Explanation: Confirms that specific molecular abnormalities including collagen VII defects determine EB subtypes.


HGNC.SYMBOL:LAMB3

[PMID:20301304] [SUPPORT] biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Supports LAMB3 as one of the established causative genes for junctional epidermolysis bullosa.


HGNC.SYMBOL:LAMA3

[PMID:19945616] [SUPPORT] this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332 --- Explanation: Supports LAMA3 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.


HGNC.SYMBOL:LAMC2

[PMID:19945616] [SUPPORT] this devastating condition is most often caused by homozygous null mutations in the genes LAMA3, LAMB3, or LAMC2, each encoding for 1 of the 3 chains of the heterotrimer laminin-332 --- Explanation: Supports LAMC2 as a causative laminin-332 chain gene in junctional epidermolysis bullosa.


HGNC.SYMBOL:COL17A1

[PMID:20301304] [SUPPORT] biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Supports COL17A1 as one of the established causative genes for junctional epidermolysis bullosa.


HGNC.SYMBOL:ITGA6

[PMID:32973163] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: Supports ITGA6 as part of the adhesion-gene set underlying EB, consistent with its role in JEB with pyloric atresia.


HGNC.SYMBOL:ITGB4

[PMID:20301304] [SUPPORT] biallelic pathogenic variants in one of the genes associated with JEB: COL17A1, ITGB4, LAMA3, LAMB3, or LAMC2 --- Explanation: Supports ITGB4 as one of the established causative genes for junctional epidermolysis bullosa.


HGNC.SYMBOL:FERMT1

[PMID:32973163] [SUPPORT] EB simplex, junctional EB, dystrophic EB and Kindler EB --- Explanation: Confirms Kindler EB as one of the four major EB categories in the consensus classification.


MONDO:0017610

[PMID:20301543] [SUPPORT] Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma --- Explanation: GeneReviews confirms non-scarring blisters from minor mechanical trauma as the hallmark of EBS.

[PMID:32973163] [SUPPORT] Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Nature Reviews Disease Primers confirms blister formation from minimal trauma as the defining feature of EB.


MONDO:0017610

[PMID:8586658] [SUPPORT] after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates --- Explanation: Demonstrates thermal instability of mutant keratin filaments, providing the molecular basis for heat-exacerbated blistering.


MONDO:0017610

[PMID:20301543] [SUPPORT] Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation --- Explanation: GeneReviews confirms palmoplantar keratoderma as an additional feature of EBS.


MONDO:0017610

[PMID:34830328] [SUPPORT] Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes --- Explanation: Confirms that mutation location determines severity of structural disarrangement, explaining the severe herpetiform phenotype in Dowling-Meara EBS.


MONDO:0017610

[PMID:34572129] [SUPPORT] PLEC mutations lead to EBS with nail dystrophy --- Explanation: Confirms nail dystrophy as a recognized feature of PLEC-associated EBS.


MONDO:0017610

[PMID:20301543] [SUPPORT] Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation --- Explanation: GeneReviews lists milia as an additional feature of EBS.


MONDO:0017610

[PMID:34572129] [SUPPORT] The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness --- Explanation: Confirms progressive muscle weakness as a defining feature of EBS-MD.

[PMID:34572129] [SUPPORT] Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates --- Explanation: Confirms dystrophic muscle pathology in both human EBS-MD patients and plectin-deficient mouse models.


MONDO:0017610

[PMID:22277943] [INDIRECT EVIDENCE] [SUPPORT] Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis and related epithelia --- Explanation: Confirms K5/K14 as the obligate IF pair in basal keratinocytes and dominant mutations as the cause of EBS.

[PMID:30078200] [INDIRECT EVIDENCE] [SUPPORT] the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14) --- Explanation: Confirms KRT5 and KRT14 defects as the primary molecular basis of EBS.


MONDO:0017610


MONDO:0017610

[PMID:22277943] [INDIRECT EVIDENCE] [SUPPORT] Defects in K5-K14 filament network architecture cause basal keratinocytes to become fragile, and account for their rupture upon exposure to mechanical trauma --- Explanation: Confirms that disrupted keratin filament architecture causes basal keratinocyte fragility and rupture.

[PMID:34830328] [INDIRECT EVIDENCE] [SUPPORT] Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs --- Explanation: Confirms that mutant keratins form aggregates with impaired dynamics, triggering downstream ER stress signaling.


MONDO:0017610

[PMID:16098032] [INDIRECT EVIDENCE] [SUPPORT] Epidermolysis bullosa simplex (EBS) is a mechano-bullous disorder characterized by intraepidermal blistering within the basal keratinocytes as a result of trauma to the skin --- Explanation: Confirms intraepidermal blistering within basal keratinocytes as the hallmark of EBS.

[PMID:34830328] [INDIRECT EVIDENCE] [SUPPORT] Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures --- Explanation: Confirms that keratin mutations lead to intraepidermal rupture.


MONDO:0017610

[PMID:34572129] [INDIRECT EVIDENCE] [SUPPORT] Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies --- Explanation: Confirms plectin as a cytoskeletal crosslinker whose mutations cause plectinopathies including EBS-MD.

[PMID:25530118] [INDIRECT EVIDENCE] [SUPPORT] Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein --- Explanation: Confirms plectin deficiency causes EBS with multi-organ involvement including skin and muscle.


MONDO:0017610

[PMID:8586658] [INDIRECT EVIDENCE] [SUPPORT] after thermal stress a reduced stability of the keratin filaments was demonstrable in the epidermolysis bullosa simplex cell lines, with filaments breaking into aggregates --- Explanation: Demonstrates that thermal stress causes keratin filament breakdown into aggregates in EBS cell lines, explaining heat-exacerbated blistering.


MAXO:0000950

[PMID:20301543] [SUPPORT] Supportive care to protect the skin from blistering; use of dressings that will protect the skin and promote healing of wounds --- Explanation: GeneReviews confirms supportive wound care as the primary management strategy for EBS.


MAXO:0000950

[PMID:20301543] [SUPPORT] Excessive heat exposure may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin --- Explanation: GeneReviews lists heat exposure and skin trauma as agents to avoid in EBS management.


MAXO:0000950

[PMID:20301543] [SUPPORT] Aluminum chloride (20%) applied to palms and soles can reduce sweating and therefore minimize blister formation in some individuals with EBS --- Explanation: GeneReviews confirms aluminum chloride antiperspirant as a treatment to reduce sweating-induced blistering.


MAXO:0000950

[PMID:20301543] [SUPPORT] Identification and management of specific causes of pain and itching; management with a pain specialist as needed --- Explanation: GeneReviews confirms pain and itch management as part of EBS care.


MAXO:0000011

[PMID:20301543] [SUPPORT] appropriate footwear and physical therapy to preserve ambulation --- Explanation: GeneReviews confirms physical therapy to preserve ambulation as part of EBS management.


MAXO:0000079

[PMID:16098032] [SUPPORT] These findings have implications for genetic counseling and prenatal diagnosis for EBS --- Explanation: Confirms the importance of genetic counseling for EBS families, particularly given de novo mutations and mixed inheritance patterns.


MAXO:0000058

[PMID:29410318] [SUPPORT] Of the patients receiving diacerein, 86% in episode 1 and 37.5% in episode 2 met the primary end point (vs 14% and 17% with placebo, respectively). This effect was still significant after the follow-up --- Explanation: Phase 2/3 crossover trial demonstrating diacerein efficacy in reducing EBS blisters compared to placebo.

[PMID:37276163] [PARTIAL] Although there was no significant difference in outcomes between the groups, further study may elucidate the effects of diacerein on EBS lesions, especially in patients with severe EBS --- Explanation: Larger RCT (n=54) did not meet primary endpoint overall, though post hoc analysis suggested benefit in severe EBS subgroup.


MAXO:0000058

[PMID:17724334] [SUPPORT] treatment with a pharmacological activator of Nrf2, two transcription factors eliciting distinct transcriptional programs, alleviates the blistering caused by a K14 deficiency in an EBS mouse model, correlating with K17 induction in basal epidermal keratinocytes. Nrf2 induction is brought about by treatment with sulforaphane, a natural product --- Explanation: Mouse model demonstrates sulforaphane activates Nrf2 to induce compensatory K17 expression in basal keratinocytes, alleviating blistering in K14-deficient EBS.


HGNC.SYMBOL:KRT5

[PMID:16098032] [SUPPORT] 18 were found to harbor heterozygous mutations in the keratin 5 or keratin 14 genes, KRT5 and KRT14, respectively --- Explanation: Confirms heterozygous KRT5 mutations as a cause of EBS.

[PMID:30078200] [SUPPORT] the most important and most commonly occurring molecular defects in these patients are the defects of keratins 5 and14 (KRT5 and KRT14) --- Explanation: Confirms KRT5 as one of the two principal genes mutated in EBS.


HGNC.SYMBOL:KRT14

[PMID:22277943] [SUPPORT] Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5 --- Explanation: Confirms dominant KRT14 mutations as a major cause of EBS.

[PMID:16098032] [SUPPORT] many cases result from de novo mutations in KRT5 and KRT14 genes --- Explanation: Confirms that many EBS cases arise from de novo KRT14 mutations.


HGNC.SYMBOL:PLEC

[PMID:34572129] [SUPPORT] Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies --- Explanation: Confirms PLEC mutations as causative for plectinopathies including EBS-MD.

[PMID:16098032] [SUPPORT] in 14 cases, the disease was associated with mutations in both alleles of the plectin gene --- Explanation: Confirms biallelic plectin mutations in EBS patients, establishing recessive inheritance.


HGNC.SYMBOL:DST

[PMID:20301543] [SUPPORT] biallelic pathogenic variants in CD151, DST, or EXPH5 --- Explanation: GeneReviews lists DST as a gene with biallelic pathogenic variants causing autosomal recessive EBS.


HGNC.SYMBOL:EXPH5

[PMID:20301543] [SUPPORT] biallelic pathogenic variants in CD151, DST, or EXPH5 --- Explanation: GeneReviews lists EXPH5 as a gene with biallelic pathogenic variants causing autosomal recessive EBS.


hgnc:25947

[PMID:27798626] [SUPPORT] dominant mutations of KLHL24, encoding a cullin 3-RBX1 ubiquitin ligase substrate receptor, cause EB. We have identified start-codon mutations in the KLHL24 gene in five patients with EB. These mutations lead to truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than its wild-type counterpart owing to abolished autoubiquitination. We have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14 --- Explanation: Identifies KLHL24 start-codon mutations as a novel cause of EBS through stabilized truncated protein that excessively degrades KRT14.

[PMID:27889062] [SUPPORT] monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes --- Explanation: Independently confirms KLHL24 initiation codon mutations in 14 individuals with skin fragility and basal keratinocyte cleavage.


MONDO:0005027


MONDO:0005027

[PMID:39056027] [PARTIAL] Lower E/I in the left entorhinal and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short-term verbal memory. --- Explanation: Supports a memory impairment correlation in temporal lobe epilepsy, but only partially supports the broader epilepsy-level phenotype claim.


MONDO:0005027

[PMID:39056027] [INDIRECT EVIDENCE] [PARTIAL] Patients with temporal lobe epilepsy showed a significantly larger exponent, corresponding to inhibition-directed E/I balance, in bilateral frontal and temporal regions. --- Explanation: Supports excitation/inhibition imbalance in temporal lobe epilepsy, but only partially supports this broad descriptor for epilepsy overall.

[PMID:39056027] [INDIRECT EVIDENCE] [PARTIAL] Limited to patients with temporal lobe epilepsy, we detected a significant correlation between the exponent and the cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2 and PDYN genes. --- Explanation: Supports molecular correlates of E/I imbalance in temporal lobe epilepsy, but only partially supports this generalized mechanism statement.


MONDO:0005027

[PMID:35422069] [INDIRECT EVIDENCE] [SUPPORT] claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. --- Explanation: Demonstrates that BBB dysfunction occurs in human epilepsy patients and is characterized by loss of tight junction proteins.

[PMID:35422069] [INDIRECT EVIDENCE] [SUPPORT] inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. --- Explanation: Establishes causal role of BBB dysfunction in seizure generation, showing that disruption of endothelial tight junctions is sufficient to trigger spontaneous seizures.

[PMID:35422069] [INDIRECT EVIDENCE] [SUPPORT] RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. --- Explanation: Provides proof-of-concept that stabilizing the BBB through claudin-5 upregulation can prevent seizures, supporting BBB as a therapeutic target.


MONDO:0005027

[PMID:31174205] [INDIRECT EVIDENCE] [SUPPORT] Treatment with the mTORC1 inhibitor rapamycin starting after 3 weeks of age significantly prolonged the survival of Depdc5cc+ mice and partially rescued the behavioral hyperactivity. --- Explanation: Demonstrates that mTORC1 pathway hyperactivation caused by DEPDC5 loss drives epilepsy pathogenesis and that mTOR inhibition can rescue the phenotype.

[PMID:31174205] [INDIRECT EVIDENCE] [SUPPORT] Rapamycin decreased the enlarged brain size of Depdc5cc+ mice with corresponding decrease in neuronal soma size. --- Explanation: Shows that mTOR hyperactivation causes abnormal neuronal growth contributing to epileptogenesis, which can be reversed by mTOR inhibition.


HGNC.SYMBOL:SCN1A

[PMID:37812819] [SUPPORT] It is caused by haploinsufficiency of SCN1A gene encoding for the α-subunit of the voltage-gated sodium channel Nav1.1. --- Explanation: Establishes SCN1A haploinsufficiency as the genetic cause of Dravet syndrome epileptic encephalopathy.

[PMID:37812819] [SUPPORT] Induction of heterozygous Nav1.1 mutation at P30 and P60 elicited susceptibility to the development of both spontaneous and hyperthermia-induced seizures and SUDEP rates comparable to P2-induced mice, with symptom onset accompanied by the characteristic GABAergic interneuron dysfunction. --- Explanation: Demonstrates that SCN1A haploinsufficiency causes seizures through GABAergic interneuron dysfunction, and this mechanism is active throughout life, not just during development.


HGNC.SYMBOL:SCN2A

[PMID:31205438] [SUPPORT] The voltage-gated sodium channel neuronal type 2 alpha subunit (Navα1.2) encoded by the SCN2A gene causes early infantile epileptic encephalopathy (EIEE) inherited in an autosomal dominant manner. --- Explanation: Establishes SCN2A mutations as a cause of early infantile epileptic encephalopathy.


HGNC.SYMBOL:KCNQ2

[PMID:17675531] [SUPPORT] Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half of which lead to protein truncation. --- Explanation: Establishes KCNQ2 as the most common genetic cause of benign familial neonatal seizures.


HGNC.SYMBOL:GABRA1

[PMID:11992121] [SUPPORT] We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. --- Explanation: Establishes GABRA1 mutations as a cause of juvenile myoclonic epilepsy through GABA receptor dysfunction.


HGNC.SYMBOL:CDKL5

[PMID:20493745] [SUPPORT] Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. --- Explanation: Establishes CDKL5 mutations as a cause of early-onset epileptic encephalopathy.


MONDO:0018153

[PMID:32107533] [SUPPORT] Some of the most striking signs of ECD are the long bone involvement (80%-95%) --- Explanation: Long bone involvement is the most common manifestation of ECD.


MONDO:0018153


MONDO:0018153

[PMID:32107533] [SUPPORT] the hairy kidney appearance on computed tomography scan (63%) --- Explanation: Retroperitoneal/perirenal involvement with hairy kidney appearance is found in 63% of ECD patients.


MONDO:0018153

[PMID:32107533] [INDIRECT EVIDENCE] [SUPPORT] Mutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%. --- Explanation: Comprehensive review establishing MAPK pathway mutations as the molecular driver of ECD.

[PMID:32107533] [INDIRECT EVIDENCE] [SUPPORT] The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of patients with ECD, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the "L" group. Both conditions are considered inflammatory myeloid neoplasms. --- Explanation: ECD is now classified as an inflammatory myeloid neoplasm based on the discovery of clonal MAPK pathway mutations.


MONDO:0018153

[PMID:32107533] [INDIRECT EVIDENCE] [SUPPORT] Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes --- Explanation: Defines the characteristic histiocytic infiltrate of ECD.


MAXO:0000058

[PMID:25422482] [SUPPORT] All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). --- Explanation: All 8 patients with multisystemic BRAF-mutant ECD showed metabolic responses to vemurafenib.

[PMID:25422482] [SUPPORT] Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. --- Explanation: Vemurafenib shows sustained efficacy without acquired resistance in ECD.


MAXO:0000058

[PMID:32107533] [SUPPORT] Since 2012, more than 200 patients worldwide with multisystem or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. --- Explanation: MEK inhibitors are part of the targeted therapy approach for ECD.


MAXO:0000058

[PMID:32107533] [SUPPORT] Interferon-α seems to be the best initial treatment of ECD. --- Explanation: Comprehensive review identifies interferon-alpha as best initial treatment, though targeted therapies are now preferred for severe cases.


HGNC.SYMBOL:BRAF V600E

[PMID:32107533] [SUPPORT] Mutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases --- Explanation: Establishes BRAF V600E as the most common mutation in ECD.


MONDO:0001134

[PMID:38172242] [SUPPORT] Hypertension is a global health problem, with >1.3 billion individuals with high blood pressure worldwide. --- Explanation: This establishes hypertension as the defining diagnostic feature of the condition.

[PMID:38164753] [SUPPORT] Hypertension is the primary modifiable risk factor for cardiovascular, renal, and cerebrovascular diseases and is considered the main contributing factor to morbidity and mortality worldwide. --- Explanation: This confirms the clinical significance of elevated blood pressure as the primary phenotype.


MONDO:0001134


MONDO:0001134

[PMID:38172242] [SUPPORT] The activated immune cells migrate to target organs such as arteries (especially the perivascular fat and adventitia), kidneys, the heart and the brain, where they release effector cytokines that elevate blood pressure and cause vascular remodelling, renal damage, cardiac hypertrophy, cognitive impairment and dementia. --- Explanation: This confirms cardiac hypertrophy as a consequence of chronic hypertension and immune-mediated damage.


MONDO:0001134

[PMID:39765782] [SUPPORT] Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). --- Explanation: This confirms renal damage as a major consequence of chronic hypertension.

[PMID:38172242] [SUPPORT] The activated immune cells migrate to target organs such as arteries (especially the perivascular fat and adventitia), kidneys, the heart and the brain, where they release effector cytokines that elevate blood pressure and cause vascular remodelling, renal damage, cardiac hypertrophy, cognitive impairment and dementia. --- Explanation: This describes immune-mediated renal damage as a consequence of hypertension.

[PMID:38164753] [SUPPORT] Human and animal studies demonstrate that the immune system plays an important role in the etiology and pathogenesis of salt sensitivity of blood pressure, kidney damage, and vascular diseases. --- Explanation: This confirms the role of immune mechanisms in causing kidney damage in hypertension.


MONDO:0001134

[PMID:37080965] [INDIRECT EVIDENCE] [SUPPORT] The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. --- Explanation: This supports the central role of vascular dysfunction in hypertension pathophysiology.

[PMID:38172242] [INDIRECT EVIDENCE] [SUPPORT] Effector mediators impair nitric oxide bioavailability, leading to endothelial dysfunction and increased vascular contractility. --- Explanation: This describes the mechanism by which endothelial dysfunction increases vascular resistance.

[PMID:36703963] [INDIRECT EVIDENCE] [SUPPORT] Both innate and adaptive immunity are now known to promote the elevation of blood pressure by triggering vascular inflammation and microvascular remodeling. --- Explanation: This confirms the role of vascular remodeling in increasing resistance.


MONDO:0001134

[PMID:39765782] [INDIRECT EVIDENCE] [SUPPORT] Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. --- Explanation: This directly supports RAAS activation causing sodium retention and elevated blood pressure.

[PMID:39765782] [INDIRECT EVIDENCE] [SUPPORT] Oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. --- Explanation: This confirms RAAS activation as a critical mechanism in hypertension.

[PMID:37080965] [INDIRECT EVIDENCE] [SUPPORT] In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. --- Explanation: This confirms RAAS as a key upstream pathway driving hypertension.


MONDO:0001134

[PMID:38172242] [INDIRECT EVIDENCE] [SUPPORT] T cells, monocytes, macrophages, dendritic cells, B cells and natural killer cells are all implicated in hypertension. --- Explanation: This establishes the broad involvement of immune cells in hypertension.

[PMID:38172242] [INDIRECT EVIDENCE] [SUPPORT] The activated immune cells migrate to target organs such as arteries (especially the perivascular fat and adventitia), kidneys, the heart and the brain, where they release effector cytokines that elevate blood pressure and cause vascular remodelling, renal damage, cardiac hypertrophy, cognitive impairment and dementia. --- Explanation: This describes how immune cell infiltration leads to target organ damage in hypertension.

[PMID:36703963] [INDIRECT EVIDENCE] [SUPPORT] Hypertension is regarded as the most prominent risk factor for cardiovascular diseases, which have become a primary cause of death, and recent research has demonstrated that chronic inflammation is involved in the pathogenesis of hypertension. --- Explanation: This confirms the role of chronic inflammation in hypertension pathogenesis.

[PMID:38164753] [INDIRECT EVIDENCE] [SUPPORT] Elevated sodium activates antigen-presenting cells to release proinflammatory cytokines including IL (interleukin) 6, tumor necrosis factor-α, IL-1β, and accumulate isolevuglandin-protein adducts. In turn, these activate T cells release prohypertensive cytokines including IL-17A. --- Explanation: This describes the salt-sensitive immune activation pathway driving hypertension.


MONDO:0001134

[PMID:39765782] [INDIRECT EVIDENCE] [NO_EVIDENCE] Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. --- Explanation: This establishes the central role of ROS in hypertension development.

[PMID:39765782] [INDIRECT EVIDENCE] [SUPPORT] Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. --- Explanation: This confirms NOX enzymes as key sources of pathogenic ROS in hypertension.

[PMID:36703963] [INDIRECT EVIDENCE] [SUPPORT] In particular, interferon-gamma (IFN-γ) and interleukin-17 (IL-17) produced by activated T lymphocytes contribute to hypertension by inducing oxidative stress injury and endothelial dysfunction. --- Explanation: This describes how immune activation leads to oxidative stress and endothelial dysfunction.


HGNC.SYMBOL:ACE

[PMID:39765782] [SUPPORT] Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. --- Explanation: Snippet supports genetic susceptibility broadly, but does not provide ACE-specific evidence.


HGNC.SYMBOL:AGT

[PMID:39765782] [NO_EVIDENCE] Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. --- Explanation: Snippet supports genetic susceptibility broadly, but does not provide AGT-specific evidence.


HGNC.SYMBOL:ADD1


MONDO:0005029


MONDO:0005029

[PMID:41577837] [INDIRECT EVIDENCE] [PARTIAL] Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs), often associated with mutations in JAK2, CALR, and MPL. --- Explanation: This abstract links ET to JAK2/CALR/MPL mutations, supporting the JAK-STAT activation described.


MAXO:0000058


CHEBI:15365


CHEBI:44423


CHEBI:142290


HGNC.SYMBOL:JAK2


HGNC.SYMBOL:CALR


HGNC.SYMBOL:MPL


MONDO:0005029

[PMID:30969531] [PARTIAL] ET is characterized by thrombocytosis --- Explanation: Abstract notes ET is characterized by thrombocytosis.


MONDO:0012817


MONDO:0012817

[PMID:33741715] [INDIRECT EVIDENCE] [PARTIAL] Ewing sarcomas are driven by EWS-ETS fusions, most commonly EWS-FLI1, which promotes widespread metabolic reprogramming, including activation of serine biosynthesis. --- Explanation: This supports EWS-FLI1 as a key driver fusion in Ewing sarcoma, but not all specific structural details in the descriptor.


MONDO:0012817

[PMID:33741715] [INDIRECT EVIDENCE] [PARTIAL] We identified and validated an EWS-FLI1 binding site at the ATF4 promoter, indicating that the fusion can directly activate ATF4 transcription. --- Explanation: Supports direct transcriptional activation by EWS-FLI1, but not all specific enhancer-mechanism details in the descriptor.


MAXO:0000647


CHEBI:28445


CHEBI:28748


CHEBI:4026


CHEBI:5864


CHEBI:4911


MAXO:0000004


MAXO:0000014


HGNC.SYMBOL:EWS-FLI1 Fusion


MONDO:0012817

[PMID:35117540] [SUPPORT] Ewing sarcoma is a small round cell tumor of bone or soft tissue --- Explanation: Abstract defines Ewing sarcoma as a small round cell tumor of bone or soft tissue.


MONDO:0007844

[PMID:20301509] [SUPPORT] Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. --- Explanation: Confirms delayed puberty as a cardinal feature.


MONDO:0007844

[PMID:20301509] [SUPPORT] IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. --- Explanation: Establishes anosmia frequency at approximately 60%.


MONDO:0007844

[PMID:20301509] [SUPPORT] Infant boys with congenital IGD often have micropenis and cryptorchidism. --- Explanation: Micropenis is a recognized feature in infant boys with congenital IGD.


MONDO:0007844

[PMID:20301509] [SUPPORT] Infant boys with congenital IGD often have micropenis and cryptorchidism. --- Explanation: Cryptorchidism is a recognized feature in infant boys with congenital IGD.


MONDO:0007844

[PMID:20301509] [SUPPORT] Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. --- Explanation: Describes the hypogonadal phenotype in adult males.


MONDO:0007844

[PMID:20301509] [SUPPORT] Adult females have little or no breast development and primary amenorrhea. --- Explanation: Confirms primary amenorrhea as a feature in affected females.


MONDO:0007844

[PMID:20301509] [SUPPORT] Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed. --- Explanation: Indicates decreased bone mass as a secondary complication requiring management.


MONDO:0007844

[PMID:20301509] [SUPPORT] diminished libido, erectile dysfunction, and infertility. --- Explanation: Infertility is a core feature of IGD.


MONDO:0007844

[PMID:20301509] [SUPPORT] Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. --- Explanation: Describes the specific growth pattern in IGD.


MONDO:0007844

[PMID:20301509] [INDIRECT EVIDENCE] [SUPPORT] Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown. --- Explanation: GeneReviews confirms the genetic heterogeneity of IGD, with FGFR1 being one of the established causative genes.


MONDO:0007844


MONDO:0007844

[PMID:20301509] [INDIRECT EVIDENCE] [SUPPORT] Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. --- Explanation: Defines the core endocrine defect of IGD.


MAXO:0000058

[PMID:20301509] [SUPPORT] gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females --- Explanation: Describes standard hormone replacement approach for males and females with IGD.


MAXO:0000058

[PMID:20301509] [SUPPORT] stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy --- Explanation: Gonadotropin therapy is the standard approach for inducing fertility in IGD.


hgnc:3688

[PMID:20301509] [SUPPORT] Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown. --- Explanation: FGFR1 is one of more than 25 genes established to cause IGD.


MONDO:0007844

[PMID:20301509] [SUPPORT] IGD can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. --- Explanation: GeneReviews confirms autosomal dominant as one inheritance pattern for IGD.


MONDO:0003210


MONDO:0003210

[PMID:36535760] [INDIRECT EVIDENCE] [PARTIAL] Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%). --- Explanation: Supports FGFR2 fusions as frequent alterations in intrahepatic cholangiocarcinoma.


MAXO:0000058


NCIT:C121553


NCIT:C114283


NCIT:C88302


MAXO:0000647


NCIT:C103194


CHEBI:27899


MAXO:0000004


HGNC.SYMBOL:FGFR2 Fusions

[PMID:35871236] [PARTIAL] Recently, several actionable genetic aberrations were identified with significant enrichment in intrahepatic CCA, including FGFR2 gene fusions with a prevalence of 10-15%. --- Explanation: Abstract reports FGFR2 fusion prevalence in intrahepatic cholangiocarcinoma.


HGNC.SYMBOL:FGFR2 Mutations/Amplifications


HGNC.SYMBOL:FGFR Resistance Mutations


MONDO:0003210

[PMID:12901270] [PARTIAL] Histologically, 90-95% of CC are well differentiated --- Explanation: Abstract notes that the majority of cholangiocarcinomas are well differentiated.


MONDO:0040679


NCIT:C103273


HGNC.SYMBOL:FGFR3

[PMID:31264434] [PARTIAL] Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib. --- Explanation: Supports clinically relevant FGFR3 mutations in urothelial carcinoma.


MONDO:0040679

[PMID:21566415] [SUPPORT] carcinomas are classified as urothelial carcinoma (UC) --- Explanation: Abstract states that bladder carcinomas are classified as urothelial carcinoma.


MONDO:0010232

[PMID:17357080] [SUPPORT] an X-linked recessive form of chronic idiopathic intestinal pseudo-obstruction (CIIPX) maps to Xq28 --- Explanation: Identifies CIIPX as the primary phenotype.


MONDO:0010232

[PMID:18854860] [SUPPORT] several male patients had presented with intestinal pseudo-obstruction or bladder distension --- Explanation: Bladder distension occurs alongside intestinal pseudo-obstruction.


MONDO:0010232

[PMID:17357080] [SUPPORT] the affected male bearing the FLNA deletion had signs of CNS involvement and potentially has PVNH --- Explanation: CNS involvement including possible PVNH in FLNA-CIPO patient.


MONDO:0010232

[PMID:17357080] [INDIRECT EVIDENCE] [SUPPORT] one affected male from a large CIIPX-affected kindred bears a 2-bp deletion in exon 2 of the FLNA gene --- Explanation: Identifies FLNA loss-of-function mutation as causative for X-linked chronic intestinal pseudo-obstruction.

[PMID:17357080] [INDIRECT EVIDENCE] [SUPPORT] the filamin protein is present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts --- Explanation: Demonstrates that the truncated filamin A protein has abnormal cytoskeletal function.

[PMID:17357080] [INDIRECT EVIDENCE] [SUPPORT] the filamin N terminal region between the initial two methionines is crucial for proper enteric neuron development --- Explanation: Establishes the N-terminal region of FLNA as critical for enteric neuron development.


MONDO:0010232


MONDO:0010232

[PMID:18854860] [INDIRECT EVIDENCE] [SUPPORT] We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families. --- Explanation: Supports FLNA involvement in both bowel and bladder dysfunction.


MAXO:0000088


MAXO:0000079


hgnc:3754

[PMID:17357080] [SUPPORT] Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. --- Explanation: Title of landmark paper establishing FLNA as causative for CIIPX.

[PMID:18854860] [SUPPORT] The two remaining families were shown to have intragenic duplications of FLNA only. --- Explanation: FLNA intragenic duplications as an alternative mutational mechanism.


MONDO:0100415


MONDO:0100415

[PMID:41228209] [INDIRECT EVIDENCE] [SUPPORT] In acute myeloid leukemia (AML), FLT3 mutations-most commonly internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) substitutions-are among the most frequent genetic alterations, driving constitutive activation of proliferative and antiapoptotic pathways and conferring adverse prognosis. --- Explanation: This abstract describes FLT3-ITD/TKD mutations driving constitutive activation in AML, matching the mechanism described.


MAXO:0000058


CHEBI:63452


CHEBI:145372


MAXO:0000647


MAXO:0000747


HGNC.SYMBOL:FLT3-ITD


HGNC.SYMBOL:FLT3-TKD


MONDO:0100415

[PMID:23590662] [SUPPORT] myeloblasts in the blood or bone marrow. --- Explanation: Abstract notes myeloblasts in the blood or bone marrow in AML.


MONDO:0019503

[PMID:19708017] [SUPPORT] isolated cataract (cerulean type and early onset adult nuclear and cortical cataract) --- Explanation: Documents cataract subtypes observed with dominant FOXE3 mutations.


MONDO:0019503

[PMID:16826526] [SUPPORT] Congenital primary aphakia (CPA) is a rare developmental disorder characterized by the absence of lens --- Explanation: Defines congenital primary aphakia as the hallmark phenotype of homozygous FOXE3 loss.


MONDO:0019503

[PMID:19708017] [SUPPORT] we identify new recessive FOXE3 mutations causative for microphthalmia, sclerocornea, primary aphakia, and glaucoma --- Explanation: Microphthalmia is a consistent feature of recessive FOXE3 disease.


MONDO:0019503

[PMID:20664696] [SUPPORT] Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea --- Explanation: Highlights sclerocornea as a prominent presenting feature of homozygous FOXE3 mutations.


MONDO:0019503

[PMID:11980846] [SUPPORT] The phenotype is variable but typically consists of the equivalent of Peters' anomaly in humans, with central corneal opacity, keratolenticular adhesion, and, in some cases, anterior polar cataract --- Explanation: Mouse model of Foxe3 haploinsufficiency demonstrates Peters anomaly phenotype.

[PMID:19708017] [SUPPORT] the dominant mutations were penetrant, they gave rise to highly variable phenotypes including iris and chorioretinal colobomas, Peters' anomaly, and isolated cataract --- Explanation: Documents Peters anomaly in human patients with heterozygous FOXE3 mutations.


MONDO:0019503

[PMID:16826526] [SUPPORT] This original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histological criterion for CPA --- Explanation: Anterior segment aplasia is the secondary consequence of primary lens failure in FOXE3 disease.


MONDO:0019503

[PMID:19708017] [SUPPORT] recessive FOXE3 mutations causative for microphthalmia, sclerocornea, primary aphakia, and glaucoma --- Explanation: Glaucoma is part of the recessive FOXE3 phenotypic spectrum.


MONDO:0019503

[PMID:10890982] [INDIRECT EVIDENCE] [SUPPORT] During development Foxe3 is expressed in all undifferentiated lens tissues, and is turned off upon fiber cell differentiation --- Explanation: Establishes Foxe3 as a lens-specific developmental transcription factor required for proper lens formation.

[PMID:17344231] [INDIRECT EVIDENCE] [SUPPORT] Foxe3 had been shown to play a crucial role in vertebrate lens formation and this gene is one of the earliest integrators of several signaling pathways that cooperate to form a lens --- Explanation: Reviews the central role of FOXE3 in integrating lens developmental signaling pathways.

[PMID:16826526] [INDIRECT EVIDENCE] [SUPPORT] it indicates a possible critical role for FOXE3 very early in the lens developmental program, perhaps earlier than any role recognized elsewhere for this gene --- Explanation: Suggests FOXE3 plays a very early role in lens development, consistent with aphakia as the null phenotype.


MONDO:0019503


MONDO:0019503

[PMID:19708017] [INDIRECT EVIDENCE] [SUPPORT] expression of FOXE3 restricted to lens tissue, predominantly in the anterior epithelium, suggesting that the extralenticular phenotypes caused by FOXE3 mutations are most likely to be secondary to abnormal lens formation --- Explanation: Demonstrates that extralenticular phenotypes are secondary to primary lens defects, since FOXE3 expression is restricted to the lens.

[PMID:11980846] [INDIRECT EVIDENCE] [SUPPORT] Approximately 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects --- Explanation: Mouse haploinsufficiency model shows secondary corneal defects arising from primary lens abnormalities.


hgnc:3808

[PMID:10890982] [SUPPORT] During development Foxe3 is expressed in all undifferentiated lens tissues, and is turned off upon fiber cell differentiation --- Explanation: Original discovery that Foxe3 maps to the dysgenetic lens locus and is critical for lens development.

[PMID:17344231] [SUPPORT] Foxe3 had been shown to play a crucial role in vertebrate lens formation and this gene is one of the earliest integrators of several signaling pathways that cooperate to form a lens --- Explanation: Review confirming FOXE3 as a central integrator of lens developmental signaling.


MONDO:0019503

[PMID:19708017] [SUPPORT] we report two further novel heterozygous mutations segregating in a dominant fashion in two different families --- Explanation: Identifies dominant FOXE3 mutations segregating in families with variable anterior segment phenotypes.

[PMID:11980846] [SUPPORT] Haploinsufficiency of Foxe3 in a mouse model causes anterior segment dysgenesis similar to Peters' anomaly --- Explanation: Mouse model demonstrates that Foxe3 haploinsufficiency recapitulates dominant anterior segment dysgenesis.


MONDO:0019503

[PMID:16826526] [SUPPORT] a null mutation in the FOXE3 gene segregates and, in the homozygous state, produces the mutant phenotype in this family --- Explanation: Demonstrates autosomal recessive inheritance of congenital primary aphakia caused by homozygous FOXE3 null mutation.

[PMID:20361012] [SUPPORT] FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia --- Explanation: Confirms autosomal recessive inheritance of FOXE3-related primary aphakia in an independent family.


MONDO:0010526

[PMID:31939530] [SUPPORT] The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain --- Explanation: Establishes acroparesthesia and neuropathic pain as early clinical manifestations in Fabry disease


MONDO:0010526

[PMID:31939530] [SUPPORT] Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency --- Explanation: Identifies angiokeratomas as a characteristic progressive clinical manifestation of Fabry disease


MONDO:0010526

[PMID:39100494] [PARTIAL] This study focuses on genome-wide expression analysis in an FD human podocyte model to gain insights into the underlying mechanisms of podocyte dysfunction --- Explanation: Supports podocyte dysfunction mechanisms, but does not directly report clinical proteinuria frequency.


MONDO:0010526

[PMID:31939530] [SUPPORT] Subsequently, symptoms related to progressive impairment appear...proteinuria, and renal insufficiency. The latter being the main cause of death in FD --- Explanation: Identifies progressive renal failure as the primary cause of death in Fabry disease


MONDO:0010526

[PMID:33602475] [SUPPORT] Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death --- Explanation: Confirms that left ventricular hypertrophy is a major cardiac manifestation of Fabry disease


MONDO:0010526

[PMID:31939530] [NO_EVIDENCE] Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency --- Explanation: Snippet supports myocardial fibrosis but does not directly report arrhythmia as a phenotype.


MONDO:0010526

[PMID:35652398] [NO_EVIDENCE] A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity --- Explanation: Snippet discusses treatment approach and does not directly support stroke frequency/risk.


MONDO:0010526

[PMID:31939530] [INDIRECT EVIDENCE] [PARTIAL] Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system --- Explanation: Supports the core GLA deficiency/Gb3 accumulation mechanism, but not the full lyso-Gb3 cytotoxicity and autophagy-ATP details.


MONDO:0010526


MONDO:0010526

[PMID:39978321] [INDIRECT EVIDENCE] [PARTIAL] Missense variants in the coding sequence of the GLA gene would generate the misfolding of the altered protein alpha-galactosidase A. Emergence of misfolded proteins may generate stress of the endoplasmic reticulum, leading to induction of the unfolded protein response (UPR) --- Explanation: Supports ER stress/UPR induction from misfolded GLA variants, but does not fully establish all downstream pathway details stated.


MONDO:0010526

[PMID:29530533] [INDIRECT EVIDENCE] [NO_EVIDENCE] Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications --- Explanation: Snippet is general disease background and does not directly support mitochondrial dysfunction or oxidative stress mechanisms.


MONDO:0010526

[PMID:37014703] [INDIRECT EVIDENCE] [PARTIAL] Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT --- Explanation: Shows that α-synuclein accumulation impairs lysosomal function and autophagy in Fabry podocytes, and that SNCA is a key driver of injury beyond Gb3 accumulation


MONDO:0010526

[PMID:38304433] [INDIRECT EVIDENCE] [SUPPORT] we demonstrate strong activation of the complement system in 17 classical male FD patients with either missense or nonsense mutations before and after ERT as evidenced by high C3a and C5a serum levels --- Explanation: Demonstrates that complement system is strongly activated in Fabry disease patients, supporting the role of innate immune activation in pathogenesis

[PMID:38932991] [INDIRECT EVIDENCE] [PARTIAL] Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms --- Explanation: Confirms inflammation as a key pathogenic mechanism in Fabry disease, with emphasis on innate immune response


MONDO:0010526

[PMID:31939530] [INDIRECT EVIDENCE] [NO_EVIDENCE] Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency --- Explanation: Snippet lists clinical manifestations but does not directly support the specific endothelial dysfunction/vascular remodeling mechanisms stated.


MONDO:0010526

[PMID:38304433] [INDIRECT EVIDENCE] [PARTIAL] we found increased IL-6, IL-10 and TGF-ß1 serum levels in FD patients --- Explanation: Supports elevated profibrotic cytokine signaling (TGF-β1), but not the full extracellular matrix remodeling cascade described.


MAXO:0000933

[PMID:37014703] [PARTIAL] long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury --- Explanation: Shows that ERT reduces substrate accumulation but cannot fully reverse organ damage in Fabry nephropathy


MAXO:0000933

[PMID:37014703] [INDIRECT EVIDENCE] [PARTIAL] long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury --- Explanation: Shows that ERT reduces substrate accumulation but cannot fully reverse organ damage in Fabry nephropathy


MAXO:0000933


MAXO:0000058

[PMID:40310476] [SUPPORT] if a responding ('amenable') α-galactosidase A mutation is present, oral pharmacological chaperone therapy (migalastat 123 mg, every other day) --- Explanation: Confirms migalastat is an approved oral chaperone therapy for amenable GLA mutations


MAXO:0001001

[PMID:40310476] [PARTIAL] Future therapeutic options may include substrate reduction therapy, gene therapy, messenger RNA therapy, and/or vesicle-packaged enzyme replacement therapy --- Explanation: Supports gene therapy as a future option, but not established clinical efficacy outcomes.


MAXO:0000950

[PMID:32183665] [NO_EVIDENCE] The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone --- Explanation: Snippet supports disease-specific therapy standards, not the supportive-care interventions described in this item.


MAXO:0000950

[PMID:32183665] [INDIRECT EVIDENCE] [NO_EVIDENCE] The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone --- Explanation: Snippet supports disease-specific therapy standards, not the supportive-care interventions described in this item.


MAXO:0000950


HGNC.SYMBOL:GLA gene mutations

[PMID:39100494] [SUPPORT] Fabry disease (FD) is an X-linked lysosomal disease caused by an enzyme deficiency of alpha-galactosidase A (α-gal A) --- Explanation: Confirms that Fabry disease is X-linked and caused by deficiency of alpha-galactosidase A enzyme

[PMID:39609713] [SUPPORT] Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications --- Explanation: Establishes genetic testing as diagnostic gold standard and highlights need for comprehensive sequencing approaches to detect all variant types


MONDO:0021056


MONDO:0021056

[PMID:28668823] [SUPPORT] Among associated lesions in FAP, desmoid tumors represent a common possible life-threatening condition that requires special attention. They are rare tumors occurring with a particularly high incidence in FAP, especially after surgery. --- Explanation: Review confirms desmoid tumors are a serious complication of FAP with particularly high incidence after abdominal surgery.


MONDO:0021056

[PMID:28668823] [INDIRECT EVIDENCE] [SUPPORT] In agreement with Knudson's 'two-hit' theory, the inactivation of the residual APC gene in FAP is a critical step in the development of both colorectal cancer and desmoids. --- Explanation: Confirms that FAP follows the two-hit mechanism for both colorectal cancer and desmoid tumor development.


MAXO:0000004


MAXO:0001184


MAXO:0000079


MAXO:0000058


HGNC.SYMBOL:APC

[PMID:28668823] [PARTIAL] Several lines of evidence show that germline mutations affect the functional domains of the APC gene that are responsible for interactions of the transcript with β-catenin, whereas somatic second mutations involve the downstream region of the gene. --- Explanation: Supports APC domain involvement and second-hit pattern, but does not fully cover all detailed genotype-phenotype and de novo rate claims in this entry.


MONDO:0005439

[PMID:29219151] [SUPPORT] Familial hypercholesterolaemia is a common inherited disorder characterized by abnormally elevated serum levels of low-density lipoprotein (LDL) cholesterol from birth, which in time can lead to cardiovascular disease (CVD). --- Explanation: Elevated LDL cholesterol from birth is the defining feature of FH.


MONDO:0005439

[PMID:29219151] [SUPPORT] common diagnostic features are an elevated LDL cholesterol level and a family history of hypercholesterolaemia or (premature) CVD. --- Explanation: Premature cardiovascular disease is a key diagnostic feature of FH.


MONDO:0005439

[PMID:24404629] [SUPPORT] Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction --- Explanation: Confirms atherosclerotic plaque deposition in coronary arteries as a hallmark of FH.


MONDO:0005439

[PMID:24404629] [SUPPORT] increases the risk of premature cardiovascular events such as angina and myocardial infarction --- Explanation: Angina is listed as a premature cardiovascular event in FH.


MONDO:0005439

[PMID:25458642] [SUPPORT] FH accounts for approximately 5% (ie, roughly 13 000) of all annual myocardial infarctions in Americans younger than 60 years. --- Explanation: Quantifies the contribution of FH to premature myocardial infarction.

[PMID:24404629] [SUPPORT] increases the risk of premature cardiovascular events such as angina and myocardial infarction --- Explanation: Myocardial infarction is listed as a key cardiovascular event in FH.


MONDO:0005439

[PMID:24404629] [SUPPORT] Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease. --- Explanation: GeneReviews directly identifies calcific aortic valve disease as a feature of severe (biallelic) FH.


MONDO:0005439

[PMID:32205033] [SUPPORT] All FH patients are at high risk for premature cardiovascular disease (CVD) events due to their genetically determined lifelong exposure to high LDL-C levels. --- Explanation: Lifelong LDL-C exposure drives generalized atherosclerosis in FH.


MONDO:0005439

[PMID:18243212] [PARTIAL] Prevalence of PCVD was 21.9% (30.2% in males and 14.5% in women, P<0.001). Mean age of onset of cardiovascular event was 42.1 years in males and 50.8 years in females. --- Explanation: This study reports high prevalence of premature cardiovascular disease in FH generally, but does not specifically quantify peripheral arterial stenosis. Peripheral vascular involvement is inferred as part of the generalized atherosclerotic burden.


MONDO:0005439

[PMID:24404629] [SUPPORT] stroke occurs more rarely --- Explanation: GeneReviews notes stroke as a less common but recognized cardiovascular manifestation of FH.


MONDO:0005439

[DOI:10.3390/ijms25031637] [SUPPORT] a chronically elevated concentration of LDL-C in the plasma leads to the occurrence of certain abnormalities, such as xanthomas in the tendons and skin, as well as corneal arcus. --- Explanation: Tendon and skin xanthomas are characteristic manifestations of chronic LDL-C elevation.


MONDO:0005439

[PMID:24404629] [SUPPORT] Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. --- Explanation: GeneReviews confirms xanthelasma as a clinical feature of FH.


MONDO:0005439

[DOI:10.3390/ijms25031637] [SUPPORT] a chronically elevated concentration of LDL-C in the plasma leads to the occurrence of certain abnormalities, such as xanthomas in the tendons and skin, as well as corneal arcus. --- Explanation: Corneal arcus is a recognized clinical feature of FH.


MONDO:0005439

[PMID:29219151] [INDIRECT EVIDENCE] [SUPPORT] Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. --- Explanation: Confirms LDLR mutations as the primary cause with APOB and PCSK9 as additional causative genes.

[PMID:38125244] [INDIRECT EVIDENCE] [SUPPORT] Chromosome 19 codes data for low-density lipoprotein (LDL) receptor (LDLR). LDLR either reduces increased LDL levels from the circulation or maintains a normal level of LDL. --- Explanation: Describes the role of LDLR in LDL clearance and its chromosomal location.

[DOI:10.3390/ijms25031637] [INDIRECT EVIDENCE] [SUPPORT] Familial hypercholesterolemia (FH) is a genetic disorder primarily transmitted in an autosomal-dominant manner. --- Explanation: Confirms autosomal dominant transmission and reviews LDLR functional class defects.


MONDO:0005439


MONDO:0005439

[DOI:10.1073/pnas.0409736102] [INDIRECT EVIDENCE] [SUPPORT] Overexpression of PCSK9 in HepG2 cells caused a decrease in whole-cell and cell-surface LDLR levels. PCSK9 overexpression had no effect on LDLR synthesis but caused a dramatic increase in the degradation of the mature LDLR --- Explanation: Demonstrates that PCSK9 overexpression accelerates LDLR degradation without affecting synthesis.


MONDO:0005439

[PMID:38125244] [INDIRECT EVIDENCE] [SUPPORT] Plaque gets deposited in the lumen of the arteries, called atherosclerosis, which occurs at an early young age. --- Explanation: Confirms premature atherosclerosis as a consequence of elevated LDL in FH.

[DOI:10.3390/ijms25031637] [INDIRECT EVIDENCE] [SUPPORT] a chronically elevated concentration of LDL-C in the plasma leads to the occurrence of certain abnormalities, such as xanthomas in the tendons and skin, as well as corneal arcus. Nevertheless, a significantly more severe phenomenon is leading to the premature onset of cardiovascular disease (CVD) --- Explanation: Documents that chronic LDL-C elevation leads to both cutaneous manifestations and premature CVD.


MONDO:0005439

[DOI:10.3390/cells12121648] [INDIRECT EVIDENCE] [SUPPORT] Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. --- Explanation: Reviews the central role of LDLR loss-of-function in disrupting cholesterol homeostasis.


MAXO:0000058

[PMID:29219151] [SUPPORT] Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required. --- Explanation: Statins confirmed as first-line therapy with additional agents often needed.

[PMID:29219151] [SUPPORT] Lifelong LDL cholesterol-lowering treatment substantially improves CVD-free survival and longevity. --- Explanation: Confirms the critical importance of lifelong LDL-lowering therapy.


MAXO:0000058

[PMID:29219151] [SUPPORT] Statins are the first-line therapy, but additional drugs, such as ezetimibe, bile acid sequestrants, PCSK9 inhibitors and other emerging therapies, are often required. --- Explanation: Ezetimibe is listed as an important add-on therapy for FH.


MAXO:0000058

[DOI:10.1111/joim.13577] [SUPPORT] the discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. --- Explanation: Traces the rapid translation of PCSK9 genetics into therapeutic PCSK9 inhibitors.


MAXO:0000058

[PMID:32197277] [SUPPORT] Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. --- Explanation: ORION-9 phase 3 trial demonstrates significant LDL-C reduction with inclisiran in HeFH patients.


MAXO:0000058

[PMID:38341323] [SUPPORT] Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2%) --- Explanation: Pooled phase 3 data showing significant LDL-C lowering with bempedoic acid in HeFH patients.


MAXO:0000058

[DOI:10.1111/cts.13836] [SUPPORT] Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. --- Explanation: Demonstrates evinacumab mechanism and efficacy across age groups in HoFH.

[DOI:10.1161/atvbaha.123.320609] [SUPPORT] the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort --- Explanation: Long-term real-world data showing sustained LDL-C lowering and improved CV outcomes with evinacumab in HoFH.

[DOI:10.1161/circulationaha.123.065529] [SUPPORT] Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. --- Explanation: Demonstrates evinacumab efficacy in pediatric HoFH patients aged 5-11.


MAXO:0000058

[DOI:10.1093/eurheartj/ehad197] [SUPPORT] Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. --- Explanation: Lomitapide is part of the EAS-recommended multi-pronged therapy for HoFH.


MAXO:0000950

[DOI:10.1093/eurheartj/ehad197] [SUPPORT] Combination LDL-C-lowering therapy -- both pharmacologic intervention and lipoprotein apheresis (LA) -- is foundational. --- Explanation: Lipoprotein apheresis is a foundational treatment for HoFH.


MAXO:0001175

[PMID:35471728] [PARTIAL] Liver transplant did not enable attainment of recommended LDL-C targets in most patients with HoFH, and the majority of patients still required post-transplant LLT. Liver transplant was not curative in most of the patients with HoFH followed. Guidelines suggest that transplant is a treatment of last resort if contemporary treatments are not available or possible. --- Explanation: Case series of 9 HoFH patients shows liver transplant is not curative in most cases, with 33% mortality and ongoing LLT needed. Supports use as last resort only.


MAXO:0000088

[PMID:24404629] [SUPPORT] Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day) --- Explanation: GeneReviews recommends heart-healthy diet with reduced saturated fat and increased soluble fiber as prevention of primary manifestations.

[PMID:37543519] [PARTIAL] we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (β = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels --- Explanation: Healthy lifestyle showed no statistically significant association with LDL-C in FH (P=0.54), consistent with the genetic basis of hypercholesterolemia. However, favorable associations with HbA1c and trends for HDL-C suggest dietary modification benefits other CVD risk factors even if LDL-C reduction is modest.


MAXO:0000065

[PMID:24404629] [SUPPORT] increased physical activity --- Explanation: GeneReviews lists increased physical activity as prevention of primary manifestations in FH.

[PMID:37543519] [SUPPORT] A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity) --- Explanation: Physical activity (>=150 min/week) is a component of healthy lifestyle favorably associated with CVD risk factors in FH.


MAXO:0000081

[PMID:17054804] [SUPPORT] it appears to take 6 to 9 years before the excess risk is reduced to zero. The risk of atherosclerotic events due to smoking was estimated as 2.1 (95% confidence interval 1.5; 2.9). --- Explanation: Smoking doubles atherosclerotic event risk in FH; cessation reduces excess risk over 6-9 years, emphasizing the importance of early cessation.

[PMID:24404629] [SUPPORT] no smoking --- Explanation: GeneReviews lists no smoking as prevention of primary manifestations in FH.


MAXO:0000623

[PMID:24404629] [SUPPORT] Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day) --- Explanation: GeneReviews recommends specific dietary targets requiring nutritional counseling to implement effectively.


MAXO:0000079

[PMID:29219151] [SUPPORT] Cascade screening can contribute to early diagnosis of the disease in family members of an affected individual, which is crucial because familial hypercholesterolaemia can be asymptomatic for decades. --- Explanation: Cascade screening of family members is crucial for early diagnosis.

[DOI:10.1111/joim.13577] [SUPPORT] Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease. --- Explanation: Emphasizes the importance of improving prevention and early diagnosis to reduce the lifelong burden of FH.


HGNC.SYMBOL:LDLR

[PMID:29219151] [SUPPORT] Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor --- Explanation: LDLR mutations are the most frequent genetic cause of FH.

[DOI:10.3390/ijms24043224] [SUPPORT] Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). --- Explanation: Confirms that LDLR variants lead to impaired LDL uptake.


HGNC.SYMBOL:APOB

[DOI:10.3390/ijms24043224] [SUPPORT] Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). --- Explanation: APOB is one of the genes whose variants lead to impaired LDL uptake.

[PMID:29219151] [SUPPORT] mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. --- Explanation: Confirms APOB as a less frequent but established cause of FH.


HGNC.SYMBOL:PCSK9

[DOI:10.1073/pnas.0409736102] [SUPPORT] Overexpression of PCSK9 in HepG2 cells caused a decrease in whole-cell and cell-surface LDLR levels. PCSK9 overexpression had no effect on LDLR synthesis but caused a dramatic increase in the degradation of the mature LDLR --- Explanation: Demonstrates the mechanism by which PCSK9 gain-of-function mutations cause FH through increased LDLR degradation.

[DOI:10.1111/joim.13577] [SUPPORT] the discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al. --- Explanation: Traces the discovery of PCSK9 as a causative gene in FH.


HGNC.SYMBOL:LDLRAP1

[DOI:10.3390/ijms24043224] [SUPPORT] Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. --- Explanation: Confirms LDLRAP1 as the cause of autosomal recessive FH.


HGNC.SYMBOL:APOE

[DOI:10.3390/ijms24043224] [SUPPORT] a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. --- Explanation: Confirms rare APOE variants as contributors to FH genetic heterogeneity.


HGNC.SYMBOL:Polygenic Hypercholesterolemia

[DOI:10.3390/ijms24043224] [SUPPORT] The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. --- Explanation: Polygenic risk scores contribute to phenotypic variability in FH.


ECTO:6000029

[PMID:15554949] [SUPPORT] smoking (RR 1.67, 95% CI 1.40-1.99) --- Explanation: Smoking is an independent CVD risk factor in FH with RR 1.67 in a cohort of 2400 FH patients.

[PMID:17054804] [SUPPORT] The risk of atherosclerotic events due to smoking was estimated as 2.1 (95% confidence interval 1.5; 2.9). --- Explanation: Smoking approximately doubles the risk of atherosclerotic events in FH patients.


ECTO:6000004

[PMID:24404629] [SUPPORT] Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus. --- Explanation: GeneReviews identifies sedentary lifestyle as an agent/circumstance to avoid in FH.

[PMID:37543519] [SUPPORT] being physically active (≥150 min/week of moderate or vigorous physical activity) --- Explanation: Physical activity is a key component of the healthy lifestyle score favorably associated with CVD risk factors in FH.


ECTO:0001082

[PMID:37543519] [SUPPORT] having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day) --- Explanation: Light to moderate alcohol consumption is included as a component of the healthy lifestyle score in FH, suggesting excessive consumption is unfavorable.


MONDO:0005439

[PMID:29219151] [SUPPORT] Most cases are caused by autosomal dominant mutations in LDLR, which encodes the LDL receptor, although mutations in other genes coding for proteins involved in cholesterol metabolism or LDLR function and processing, such as APOB and PCSK9, can also be causative, although less frequently. --- Explanation: Confirms autosomal dominant inheritance as the primary mode.


MONDO:0005439


MONDO:0018088

[PMID:21358337] [PARTIAL] Familial Mediterranean fever type 1 is characterized by recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis. --- Explanation: The literature supports that recurrent fever is a common feature of Familial Mediterranean Fever type 1, but it does not fully support that FMF should be categorized solely under systemic phenotypes.

[PMID:25832989] [PARTIAL] Familial Mediterranean fever...presents with recurrent and self-limited inflammatory attacks of fever and polyserositis along with high acute-phase reactants. --- Explanation: The literature supports that recurrent fever is a common diagnostic feature of FMF and systemically involves fever and inflammation, but it does not confirm all specified aspects of the statement.

[PMID:36688581] [PARTIAL] Higher Pras scores, earlier age of symptoms and diagnosis, more frequent arthritis and erysipelas-like erythema, and higher colchicine dose are closely associated with M694V homozygous familial Mediterranean fever patients. These patients also have mostly moderate and severe disease severity. --- Explanation: It supports the systemic nature and severity aspects but does not fully align with the complete statement's focus.

[PMID:34606655] [PARTIAL] Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. It is a clinically diagnosed disease supported by Mediterranean fever gene mutation analysis. --- Explanation: While fever is a prominent symptom, FMF is known for phenotypic heterogeneity, indicating varied systemic manifestations.


MONDO:0018088

[PMID:11411958] [SUPPORT] The arthritis was transient, monoarticular, nonerosive, and nondeforming in the majority of cases. Four patients (5.4%) had chronic arthritis, with one requiring total hip replacement. As in previous reports on arthritis of FMF, the majority of FMF patients studied in Lebanon had a transient monoarticular nonerosive and nondeforming type of arthritis affecting predominantly the large joints of the lower extremities. --- Explanation: This reference supports the statement that arthritis is a common phenotype in FMF, is transient, and affects large joints.

[PMID:33124556] [SUPPORT] More patients had arthritis in the ELE group than in the other group (p=0.011). Arthritis occurred in the ankle (77.4%), knee (19.3%) and hip (3.2%) joints. --- Explanation: This reference confirms the presence of arthritis in FMF patients, especially in large joints, supporting the statement.


MONDO:0018088

[PMID:36082189] [PARTIAL] FMF is characterised by dysregulation of the inflammatory process in the body, presenting as recurrent episodes of serositis. Patients with FMF commonly present with episodes of fever, peritonitis, synovitis, pleuritis, arthritis, and occasionally pericarditis. --- Explanation: This reference supports that peritonitis, which involves abdominal pain due to inflammation of the peritoneum, is a phenotype of FMF. However, it does not explicitly indicate a high frequency of gastrointestinal phenotypes.

[PMID:37723615] [PARTIAL] Familial Mediterranean fever (FMF) is the most prevalent hereditary autoinflammatory disease among children. Abdominal pain and various gastrointestinal system (GIS) manifestations may arise directly from FMF or concomitantly with FMF. --- Explanation: This reference supports that gastrointestinal manifestations, including abdominal pain, are phenotypes of FMF. However, it does not specify the high frequency of peritonitis.

[PMID:9562837] [SUPPORT] When a patient complains of episodic fever accompanied by unexplained arthritis, peritonitis, pleurisy, or skin rash, this disorder should be considered. --- Explanation: This reference supports that peritonitis is a common phenotype of FMF, aligning well with the statement.

[PMID:35737103] [SUPPORT] The key feature of familial Mediterranean fever is relapsing episodes of fever and serositis including peritonitis, pleurisy, or arthritis. --- Explanation: This reference clearly supports that peritonitis, involving abdominal pain due to inflammation of the peritoneum, is a key feature of FMF and occurs frequently.

[PMID:31308342] [PARTIAL] Considering the history of recurrent abdominal pain, Familial Mediterranean Fever (FMF) was considered. --- Explanation: Supports recurrent abdominal pain as a clinical clue for FMF, but does not directly establish peritonitis frequency.


MONDO:0018088

[PMID:38204312] [PARTIAL] The most common signs and symptoms are fever, abdominal pain, chest pain, and arthritis. --- Explanation: Supports frequent chest pain in FMF, but does not directly specify pleuritis as the cause.

[PMID:12092043] [SUPPORT] Lung involvement in FMF is limited mainly to transient pleuritis during acute attacks. --- Explanation: The study specifies that pleuritis, which is inflammation of the pleura, is a frequent thoracic phenotype in FMF.

[PMID:36385047] [PARTIAL] Pericarditis, pleurisy and the response to colchicine indicated FMF. --- Explanation: This study identifies pleurisy, another term for pleuritis, as a characteristic symptom in FMF patients, supporting the statement.

[PMID:36725780] [PARTIAL] Pleuritis is the only known pulmonary involvement of FMF; however, as far as we know, thoracic involvements in pleural, parenchymal, bronchial, and vascular structures have not been evaluated yet. --- Explanation: While the study acknowledges pleuritis as a known pulmonary involvement in FMF, it does not provide evidence on its frequency being "FREQUENT".


MONDO:0018088


MONDO:0018088

[PMID:12832747] [SUPPORT] Amyloidosis, causing renal failure, is one of the most severe complications of the disease. --- Explanation: The literature confirms that amyloidosis can lead to kidney failure in patients with Familial Mediterranean Fever (FMF), supporting the statement.

[PMID:23548761] [SUPPORT] Familial Mediterranean Fever and tuberculosis were the most frequent causes of amyloidosis. --- Explanation: The statement is supported as FMF is listed as one of the frequent causes of renal amyloidosis.

[PMID:21360109] [SUPPORT] The most frequent cause [of renal amyloidosis in children] is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF). --- Explanation: This confirms that FMF is a frequent cause of renal amyloidosis, thereby supporting the statement.

[PMID:33052444] [SUPPORT] Amyloidosis [...] stands out as a major complication of familial Mediterranean fever (FMF). Splenic and renal involvement is more likely in FMF-associated systemic amyloidosis. --- Explanation: The literature confirms the renal involvement in FMF-associated amyloidosis, thus supporting the statement.


MONDO:0018088

[PMID:37309906] [SUPPORT] Recurrent fever, serositis, and arthritis are common findings of the disease. In addition, musculoskeletal complaints such as exertional leg pain can be overlooked, although they are common and affect patients' quality of life. --- Explanation: The literature mentions musculoskeletal complaints, including exertional leg pain, as common in FMF, supporting the statement that myalgia is an occasional symptom.

[PMID:32895731] [SUPPORT] Protracted febrile myalgia syndrome (PFMS) is one of the rare conditions characterized by long standing severe myalgia and fever in familial Mediterranean fever (FMF) patients. --- Explanation: This reference specifically mentions severe myalgia as a symptom in FMF patients, which supports the statement.


MONDO:0018088

[PMID:16344627] [INDIRECT EVIDENCE] [PARTIAL] The spectrum of reported genetic mutations and susceptible ethnicities for the hereditary periodic fever subset of the autoinflammatory diseases has continued to expand. At the same time, the pathogeneses of many of these diseases are now understood to involve different aspects of a common pathway, largely affecting inflammatory cascades related to IL-1 or tumor necrosis factor-alpha. --- Explanation: Supports shared IL-1/TNF inflammatory pathways in hereditary periodic fever syndromes, but only indirectly supports FMF-specific pathway details.

[PMID:29148036] [INDIRECT EVIDENCE] [SUPPORT] Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). --- Explanation: This reference describes the role of pyrin in inflammasome activation and its link to FMF, supporting the statement about dysregulated inflammatory responses and recurrent inflammatory episodes.

[PMID:33026080] [INDIRECT EVIDENCE] [SUPPORT] FMF is an autoinflammatory disease characterized by recurrent attacks and increased IL-1 synthesis owing to activation of the pyrin inflammasome --- Explanation: This reference directly mentions recurrent attacks and increased IL-1 synthesis due to pyrin inflammasome activation, supporting the mechanisms described in the statement.

[PMID:32601469] [INDIRECT EVIDENCE] [SUPPORT] Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. --- Explanation: This reference supports the genetic basis of FMF involving mutations in MEFV, which leads to the dysregulated inflammatory response observed in FMF.

[PMID:29051974] [INDIRECT EVIDENCE] [SUPPORT] Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested by inflammatory attacks of peritonitis, pleuritis, pericarditis accompanied by fever and arthritis. Mutations of MEFV gene results in pyrin dysfunction, which causes uncontrolled interleukin-1 beta production and triggers the inflammatory attacks. --- Explanation: This reference supports the mechanism described in the statement, emphasizing pyrin dysfunction and the uncontrolled production of interleukin-1 beta.


MAXO:0000058

[PMID:19797919] [SUPPORT] The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2-1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF. --- Explanation: The study directly supports the statement that colchicine is a first-line treatment for preventing amyloidosis, a common complication of FMF.

[PMID:25649364] [SUPPORT] The only agent that decreases the development of amyloidosis and the frequency and severity of the episodes is colchicine, which has been used for about 40 years. --- Explanation: This reference clearly supports the claim that colchicine reduces the frequency of attacks and prevents amyloidosis, affirming its role as a first-line treatment.

[PMID:25791871] [SUPPORT] Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. --- Explanation: This indicates that colchicine is considered effective for preventing FMF attacks, supporting its position as a first-line treatment.

[PMID:17242135] [SUPPORT] The daily application of colchicine is the standard therapy for prophylaxis of attacks and amyloid deposition in familial Mediterranean fever. --- Explanation: This statement corroborates that colchicine is the standard, or first-line, therapy for preventing FMF attacks and amyloidosis.

[PMID:15720245] [SUPPORT] Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. --- Explanation: This reference supports the idea that colchicine is the primary treatment for preventing FMF attacks and associated amyloidosis.


CHEBI:23359

[PMID:19797919] [INDIRECT EVIDENCE] [SUPPORT] The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2-1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF. --- Explanation: The study directly supports the statement that colchicine is a first-line treatment for preventing amyloidosis, a common complication of FMF.

[PMID:25649364] [INDIRECT EVIDENCE] [SUPPORT] The only agent that decreases the development of amyloidosis and the frequency and severity of the episodes is colchicine, which has been used for about 40 years. --- Explanation: This reference clearly supports the claim that colchicine reduces the frequency of attacks and prevents amyloidosis, affirming its role as a first-line treatment.

[PMID:25791871] [INDIRECT EVIDENCE] [SUPPORT] Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. --- Explanation: This indicates that colchicine is considered effective for preventing FMF attacks, supporting its position as a first-line treatment.

[PMID:17242135] [INDIRECT EVIDENCE] [SUPPORT] The daily application of colchicine is the standard therapy for prophylaxis of attacks and amyloid deposition in familial Mediterranean fever. --- Explanation: This statement corroborates that colchicine is the standard, or first-line, therapy for preventing FMF attacks and amyloidosis.

[PMID:15720245] [INDIRECT EVIDENCE] [SUPPORT] Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. --- Explanation: This reference supports the idea that colchicine is the primary treatment for preventing FMF attacks and associated amyloidosis.


MAXO:0000058

[PMID:28362189] [SUPPORT] The accumulating data indicates that anti IL-1 drugs are effective in treating colchicine resistant FMF cases and improving their quality of life. --- Explanation: The reference supports the use of anti-IL-1 therapy for treating colchicine-resistant FMF cases.

[PMID:30338514] [PARTIAL] For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, canakinumab, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial. --- Explanation: Provides mixed, tentative treatment options; this is partial support for anti-IL-1 use in colchicine-resistant FMF.

[PMID:36161616] [SUPPORT] Anti IL-1 therapy is useful in suppressing attacks in FMF patients with colchicine resistance. --- Explanation: The study supports the effectiveness of anti-IL-1 therapy in managing inflammation in colchicine-resistant FMF patients.

[PMID:27860460] [SUPPORT] In this randomized controlled trial, anakinra appears to be an effective and safe treatment for colchicine-resistant FMF. --- Explanation: The reference provides evidence from a randomized controlled trial supporting the effectiveness of anakinra, an anti-IL-1 therapy, in colchicine-resistant FMF patients.


MAXO:0000058

[PMID:37752496] [REFUTE] These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics. --- Explanation: The literature does not mention NSAIDs as a treatment path for symptom relief during acute attacks of Familial Mediterranean Fever. The focus is on colchicine and biological therapy.

[PMID:36945975] [NO_EVIDENCE] Mean age of the overall group was 38.2 +/- 11.7 years (62.4% female, 37.6% male). Two hundred and twenty-seven patients were treated with colchicine, 97 patients with colchicine plus Interleukin-1 (IL-1) antagonist, and 22 only with IL-1 antagonist (67.1%, 26.3%, 6.64% in order). --- Explanation: There is no mention of NSAIDs being used for symptom relief during acute attacks in FMF patients. The treatments focus on colchicine and IL-1 antagonist.


MAXO:0000088

[PMID:38488998] [PARTIAL] Patients can significantly decrease the number of familial Mediterranean fever attacks they experience by managing psychological stress and avoiding physical factors such as cold exposure and fatigue. --- Explanation: The literature supports the management of psychological stress and avoiding physical factors as triggers but does not explicitly mention infections.

[PMID:26324575] [PARTIAL] Triggers of this illness include many things, such as cold or stress. --- Explanation: The literature mentions stress as a trigger but does not provide exhaustive confirmation about infections as triggers or other preventive lifestyle modifications.


HGNC.SYMBOL:MEFV

[PMID:28154935] [SUPPORT] Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction. --- Explanation: Mutations in the MEFV gene result in increased activation of pyrin, causing excessive inflammation.

[PMID:25307949] [SUPPORT] Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever (FMF). Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells. --- Explanation: This article discusses the role of pyrin in inducing inflammatory responses, supporting the effect of MEFV gene mutations in causing excessive inflammation.

[PMID:36889987] [PARTIAL] MEFV gene mutation spectrum in patients with familial mediterranean fever --- Explanation: This supports MEFV mutation involvement in FMF, but the quoted text alone does not establish the detailed gain-of-function/pyrin-threshold mechanism.


HGNC.SYMBOL:PKN1


HGNC.SYMBOL:PKN2


HGNC.SYMBOL:RHOA


MONDO:0019391

[PMID:35596788] [SUPPORT] Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC).


MONDO:0019391

[PMID:24037726] [SUPPORT] It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. --- Explanation: Clinical description confirming that increased leukemia occurrence is a defining phenotype of FA.


MONDO:0019391

[PMID:24037726] [SUPPORT] It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. --- Explanation: Progressive bone marrow failure is a cardinal feature of FA leading to aplastic anemia.


MONDO:0019391

[PMID:20301575] [SUPPORT] Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia --- Explanation: GeneReviews documents progressive bone marrow failure with thrombocytopenia and leukopenia as typical hematologic manifestations.


MONDO:0019391