MAXO:0001155

[PMID:31824186] [SUPPORT] Ocular complications such as myopia have been reported in 45% of patients but retinal detachment is less frequent (12%) than in type 1 Strickler syndrome. --- Explanation: Review quantifying the frequency of myopia and retinal detachment in SEDC, establishing the need for regular ophthalmologic surveillance.

[PMID:6807266] [SUPPORT] Eighteen patients had ocular changes associated with spondyloepiphyseal dysplasia congenita, a rare cause of congenital dwarfism with normal mental development. Seven patients had nonprogressive myopia of 5.00 or more diopters. Vitreoretinal degeneration was encountered in six patients with high myopia, and vitreous syneresis was present in all patients. --- Explanation: Ophthalmic case series systematically documenting the vitreoretinal abnormalities in SEDC patients, supporting the need for ongoing eye surveillance.


MAXO:0000950

[PMID:10743764] [SUPPORT] Hearing loss has been reported to occur in 25 to 30% of affected patients. To date, all reports of associated hearing loss have indicated the presence of a sensorineural component. --- Explanation: Study documenting the 25-30% prevalence of hearing loss in SEDC patients, establishing the need for regular audiologic monitoring.

[PMID:31824186] [SUPPORT] Adult patients suffer from sensorineural (25% to 30% of reported cases) or less frequently mixed hearing loss. --- Explanation: Review confirming the frequency of hearing loss in SEDC and the need for ongoing audiologic assessment.


MAXO:0000079

[PMID:35581182] [SUPPORT] Genetic testing is important for early intervention for the extraskeletal complications of SEDC. --- Explanation: Study emphasizing the importance of genetic testing and counseling for SEDC families to enable early intervention for extraskeletal complications.

[PMID:1971141] [SUPPORT] Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominantly inherited chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Manifestations are present at birth. --- Explanation: Landmark study confirming autosomal dominant inheritance, which is fundamental information for genetic counseling of affected families.


MAXO:0000950

[PMID:31824186] [SUPPORT] Infants with severe SEDC are often stillborn or premature and die shortly after birth because of hypoventilation. The developing respiratory failure can be temporarily overcome only by delivering intensive ventilator support. --- Explanation: Review documenting the need for respiratory support in severe neonatal SEDC cases, noting that ventilatory support is essential for survival.


MAXO:0000058

[PMID:39953747] [SUPPORT] GH therapy resulted in height increases of 0.76 and 0.27 standard deviation scores over 3.5 and 3 years, respectively, with no significant side effects. --- Explanation: First reported evaluation of GH therapy in SEDC patients, showing modest height gains in two children with COL2A1 mutations.


hgnc:2200

[PMID:1971141] [SUPPORT] Previous evidence suggesting defects of type II collagen associated with the SEDC phenotype led us to genotype the family for various COL2A1 gene-associated RFLPs. A total of 17 affected and unaffected members of this family were studied. The family was informative for a recently discovered HinfI RFLP. No recombinants between the marker and the phenotype were found in eight informative meioses. A maximum LOD score of 3.01 was obtained at a recombination fraction of .00. --- Explanation: Landmark linkage study establishing that SEDC is caused by mutations in or near the COL2A1 gene, with a highly significant LOD score.

[PMID:26443184] [SUPPORT] Over 700 patients were recorded, harboring 415 different mutations. One-third of the mutations are dominant-negative mutations that affect the glycine residue in the G-X-Y repeats of the alpha 1 chain. --- Explanation: Comprehensive mutation database establishing the mutational spectrum of COL2A1, with dominant-negative glycine substitutions being the most common mechanism in severe phenotypes.

[PMID:31824186] [SUPPORT] In spondyloephyseal dysplasia congenita over 100 COL2A1 mutations have been described. Most common are in the triple helix (74% glycine substitutions and 10% Arg-to-Cys changes) and are dominantly inherited while only few mutations have been found involving C-peptide region. --- Explanation: Review detailing the mutational spectrum specific to SEDC, documenting that glycine and arginine-to-cysteine substitutions in the triple helix account for the vast majority of mutations.

[PMID:35581182] [SUPPORT] Spondyloepiphyseal dysplasia congenita (SEDC) (OMIM#183900) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, flattened vertebral bodies (skeletal abnormalities), and extraskeletal features, including myopia, retinal degeneration with retinal detachment, and cleft palate. SEDC is caused by a heterozygous variant in the collagen II alpha 1 (COL2A1) gene. --- Explanation: Recent Japanese cohort study of five SEDC patients, all with novel glycine substitutions, confirming the consistent genotype-phenotype pattern.


MONDO:0008471

[PMID:1971141] [SUPPORT] Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominantly inherited chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Manifestations are present at birth. --- Explanation: This linkage study confirmed the autosomal dominant inheritance pattern of SEDC in a 4-generation family.


MONDO:0008477

[PMID:39825918] [SUPPORT] Short stature and bone pain when running, walking, and climbing stairs occurred in patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia from the age of 5 years and worsened with increasing age. --- Explanation: Natural history study documenting progressive short stature in SMDK patients from age 5.

[PMID:24830047] [SUPPORT] the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. --- Explanation: GeneReviews confirms short stature as a feature of SMDK and the more severe TRPV4 skeletal dysplasias.


MONDO:0008477

[PMID:41225599] [SUPPORT] Spondylometaphyseal Dysplasia, Kozlowski Type (SMDK) is an autosomal dominant skeletal disorder characterized by marked scoliosis, platyspondyly, overfaced pedicles, and mild metaphyseal changes. --- Explanation: Confirms platyspondyly with overfaced pedicles as defining radiographic features of SMDK.

[PMID:39825918] [SUPPORT] In the radiographs of patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia, severe platyspondyly persisted into adulthood or puberty. --- Explanation: Natural history study confirming persistent severe platyspondyly through adulthood in SMDK patients.


MONDO:0008477

[PMID:39825918] [SUPPORT] The patients with spondylometaphyseal dysplasia Kozlowski type exhibited irregular proximal femora leading to destruction of the femoral head towards the end of puberty --- Explanation: Describes the progressive proximal femoral involvement and femoral head destruction specific to SMDK.


MONDO:0008477

[PMID:19232556] [SUPPORT] SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. --- Explanation: Identifies significant scoliosis as a defining characteristic of SMDK.


MONDO:0008477

[PMID:39825918] [SUPPORT] Kyphosis was more pronounced with increasing age in these two groups of patients --- Explanation: Natural history data confirming progressive kyphosis in SMDK and metatropic dysplasia patients.


MONDO:0008477


MONDO:0008477

[PMID:24830047] [SUPPORT] All TRPV4-related skeletal dysplasias are characterized by brachydactyly; the four most severe forms have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. --- Explanation: GeneReviews confirms brachydactyly as a universal feature of TRPV4 skeletal dysplasias including SMDK.


MONDO:0008477

[PMID:39825918] [SUPPORT] Short stature and bone pain when running, walking, and climbing stairs occurred in patients with spondylometaphyseal dysplasia Kozlowski type and metatropic dysplasia from the age of 5 years and worsened with increasing age. --- Explanation: Documents bone pain as a progressive symptom in SMDK patients, with onset around age 5.


MONDO:0008477

[PMID:24830047] [SUPPORT] assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia --- Explanation: GeneReviews surveillance recommendations confirm odontoid hypoplasia as a recognized complication requiring monitoring in TRPV4 skeletal dysplasias.


MONDO:0008477

[PMID:19232556] [INDIRECT EVIDENCE] [SUPPORT] Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. --- Explanation: Seminal paper establishing TRPV4 mutations as the cause of SMDK in all six tested patients.

[PMID:19232556] [INDIRECT EVIDENCE] [SUPPORT] Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. --- Explanation: In vitro functional studies demonstrating that SMDK-causing TRPV4 mutations alter basal calcium channel activity.


MONDO:0008477

[PMID:41225599] [INDIRECT EVIDENCE] [SUPPORT] Functional validation through cellular experiments revealed that the p.W785S substitution markedly reduces agonist-induced calcium influx and membrane currents, indicating a loss-of-function effect on TRPV4 channel activity. --- Explanation: Demonstrates that SMDK can also result from loss-of-function TRPV4 mutations, challenging the paradigm that only gain-of-function mutations cause TRPV4 skeletal dysplasias.


MONDO:0008477

[PMID:24644033] [INDIRECT EVIDENCE] [SUPPORT] Overexpression of a mutant TRPV4 caused a lethal skeletal dysplasia that phenocopied many abnormalities associated with metatropic dysplasia in humans, including dumbbell-shaped long bones, a small ribcage, abnormalities in the autopod, and abnormal ossification in the vertebrae. --- Explanation: Mouse model demonstrates that gain-of-function TRPV4 mutations disrupt skeletal development, recapitulating the vertebral and long bone abnormalities seen in human TRPV4 dysplasias.


MONDO:0008477

[PMID:24577120] [INDIRECT EVIDENCE] [SUPPORT] The human TRPV4(V620I) channelopathy mutation was transfected into primary porcine chondrocytes and caused significant (2.6-fold) up-regulation of follistatin (FST) expression levels. --- Explanation: Demonstrates that TRPV4 gain-of-function mutations upregulate follistatin in chondrocytes, linking calcium channelopathy to impaired skeletal development.


MONDO:0008477

[PMID:24577120] [INDIRECT EVIDENCE] [SUPPORT] FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold). Furthermore, FST-loaded microbeads decreased bone ossification in developing chick femora (6%) and tibiae (11%). --- Explanation: Shows that dysplasia-causing (but not arthropathy-causing) TRPV4 mutations specifically upregulate follistatin, and that exogenous follistatin directly reduces bone ossification in developing limbs.


MAXO:0000950

[PMID:24830047] [SUPPORT] For skeletal dysplasias, additional treatment includes physical therapy/exercise and heel cord stretching to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present. --- Explanation: GeneReviews provides current standard-of-care recommendations for TRPV4 skeletal dysplasias, centered on symptomatic multidisciplinary management.


HGNC.SYMBOL:TRPV4 Mutations

[PMID:20577006] [SUPPORT] In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. --- Explanation: Large cohort study (20 SMDK probands) establishing R594H as the recurrent SMDK hotspot and demonstrating genotype-phenotype correlation within the TRPV4 dysplasia family.

[PMID:22791502] [SUPPORT] Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. --- Explanation: Comprehensive review confirming R594 as the SMDK mutational hotspot and P799 as the metatropic dysplasia hotspot.


MONDO:0019353

[PMID:9054934] [SUPPORT] Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. --- Explanation: This landmark clinical-genetic study defines juvenile-onset macular dystrophy as a core feature of Stargardt disease.


MONDO:0019353

[PMID:28941524] [SUPPORT] Early signs by ophthalmoscopic examination may show atrophy of the RPE at the fovea (Fig. 1B) and flecks in the macula that may become more widespread over time. --- Explanation: This review directly supports central macular RPE atrophy as an early and characteristic Stargardt finding.


MONDO:0019353

[PMID:28941524] [SUPPORT] Early signs by ophthalmoscopic examination may show atrophy of the RPE at the fovea (Fig. 1B) and flecks in the macula that may become more widespread over time. --- Explanation: This review supports retinal flecks in the macula as a classic Stargardt manifestation.


MONDO:0019353

[PMID:37834872] [SUPPORT] STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. --- Explanation: This review supports progressive central visual impairment as a defining clinical feature of STGD1.


MONDO:0019353

[PMID:28941524] [SUPPORT] Visual acuity is not the only visual function affected in STGD. Deficits in color vision 33 and central visual field34 progressively increase typically accompanying a decrease in visual acuity. --- Explanation: This review supports progressive central visual field impairment corresponding to central scotoma in Stargardt disease.


MONDO:0019353

[PMID:28941524] [SUPPORT] Visual acuity is not the only visual function affected in STGD. Deficits in color vision 33 and central visual field34 progressively increase typically accompanying a decrease in visual acuity. --- Explanation: This review directly supports progressive color vision deficits in Stargardt disease.


MONDO:0019353

[PMID:28941524] [SUPPORT] AF is abnormal in STGD. Flecks are initially hyperfluorescent, reflecting the accumulation of lipofuscin in the RPE. With the progression of the RPE atrophy, the flecks become hypofluorecent. --- Explanation: This review supports abnormal autofluorescence as a core imaging phenotype linked to lipofuscin accumulation and RPE atrophy.


MONDO:0019353

[PMID:19217903] [SUPPORT] Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull's eye maculopathy in either the homozygosity or heterozygosity state. --- Explanation: This ABCA4 cohort study directly supports bull's eye maculopathy as a Stargardt-associated phenotype.


MONDO:0019353

[PMID:28941524] [SUPPORT] Early signs by ophthalmoscopic examination may show atrophy of the RPE at the fovea (Fig. 1B) and flecks in the macula that may become more widespread over time. --- Explanation: This review directly supports retinal pigment epithelial atrophy at the fovea as a Stargardt feature.


MONDO:0019353

[PMID:35608843] [PARTIAL] A pigmentary change in the posterior pole was observed in 22 of 185 patients (11.9%), and this change mimicked retinitis pigmentosa in 10 cases (45.5%). --- Explanation: This longitudinal ABCA4 cohort supports pigmentary RPE change in Stargardt retinopathy, partially supporting the retinal pigment epithelial mottling phenotype.


MONDO:0019353

[PMID:19217903] [SUPPORT] All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull's eye maculopathy without retinal flecks on FAF. --- Explanation: This study supports abnormal electrophysiology in Stargardt disease at the level of macular pattern ERG even when full-field responses remain preserved.

[PMID:29422768] [SUPPORT] The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). --- Explanation: This genotype-defined ABCA4 cohort supports abnormal full-field ERG in more severe Stargardt phenotypes.


MONDO:0019353

[PMID:28941524] [SUPPORT] The main OCT finding is a central loss of outer retinal layers (Fig. 2B); in the early-onset type, thickening of the external limiting membrane has been described.36 --- Explanation: This OCT description supports retinal thinning and central outer retinal layer loss in Stargardt disease.


MONDO:0019353

[PMID:28941524] [SUPPORT] The main OCT finding is a central loss of outer retinal layers (Fig. 2B); in the early-onset type, thickening of the external limiting membrane has been described.36 --- Explanation: This supports macular OCT evidence of central outer retinal and photoreceptor layer loss in Stargardt disease.


MONDO:0019353

[PMID:29422768] [SUPPORT] The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). --- Explanation: This ABCA4 patient cohort directly documents nyctalopia in Stargardt retinopathy, especially in severe cases with broader retinal involvement.


MONDO:0019353

[PMID:29422768] [SUPPORT] The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). --- Explanation: This ABCA4 patient cohort directly documents photophobia as part of the Stargardt clinical phenotype.


MONDO:0019353

[PMID:9054934] [INDIRECT EVIDENCE] [SUPPORT] Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to the 2-cM (centiMorgan) interval at 1p13-p21 previously shown by linkage analysis to harbour the STGD gene. --- Explanation: Landmark human genetic study linking Stargardt disease to an ABC transporter defect with lipofuscin-like material deposition.

[PMID:37940365] [INDIRECT EVIDENCE] [SUPPORT] STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). --- Explanation: This review confirms ABCA4 as the principal causative gene in autosomal recessive STGD1.


MONDO:0019353


MONDO:0019353

[PMID:28941524] [INDIRECT EVIDENCE] [SUPPORT] The malfunction of this transporter leads to accumulation of all-trans retinal, which results in increased concentration of a toxic byproduct, N-retinylidene-N-retinyl-ethanolamine (A2E), which is a major component of lipofuscin. --- Explanation: This review directly supports toxic retinoid-adduct and bisretinoid precursor formation downstream of ABCA4 dysfunction.


MONDO:0019353

[PMID:39201545] [INDIRECT EVIDENCE] [SUPPORT] The primary cause is mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts in the retinal pigment epithelium (RPE) and subsequent photoreceptor cell degeneration. --- Explanation: This human review supports the core cascade from ABCA4 mutation to toxic byproduct accumulation in RPE and downstream photoreceptor degeneration.

[PMID:38837708] [INDIRECT EVIDENCE] [SUPPORT] dysfunctional ABCA4 in STGD1 RPE cells results in intracellular accumulation of autofluorescent material and phosphatidylethanolamine (PE) --- Explanation: Patient-derived iPSC-RPE models directly show autofluorescent material accumulation caused by ABCA4 dysfunction.


MONDO:0019353

[PMID:38837708] [INDIRECT EVIDENCE] [SUPPORT] we identified cathepsin D (CatD), the primary RPE lysosomal protease, as a key molecular player contributing to endo-lysosomal dysfunction in STGD1 using a newly developed "disease-in-a-dish" RPE model from confirmed STGD1 patients --- Explanation: This study identifies cathepsin D-linked endo-lysosomal dysfunction as a core RPE mechanism in STGD1.

[PMID:38837708] [INDIRECT EVIDENCE] [SUPPORT] Induced pluripotent stem cell (iPSC)-derived RPE originating from three STGD1 patients exhibited elevated lysosomal pH, as previously reported in Abca4-/- mice. CatD protein maturation and activity were impaired in RPE from STGD1 patients and Abca4-/- mice. --- Explanation: Patient-derived RPE shows elevated lysosomal pH and impaired cathepsin D maturation, supporting lysosomal dysfunction as a distinct mechanism.


MONDO:0019353

[PMID:28941524] [INDIRECT EVIDENCE] [SUPPORT] Lipofuscin accumulates in the retinal pigment epithelium (RPE), causing RPE cell dysfunction, and consequent photoreceptor death. --- Explanation: This review directly supports RPE dysfunction as a distinct mechanistic consequence of lipofuscin accumulation.


MONDO:0019353

[PMID:39201545] [INDIRECT EVIDENCE] [SUPPORT] The primary cause is mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts in the retinal pigment epithelium (RPE) and subsequent photoreceptor cell degeneration. --- Explanation: This supports the causal link from RPE toxic byproduct accumulation to photoreceptor degeneration.

[PMID:37834872] [INDIRECT EVIDENCE] [SUPPORT] STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. --- Explanation: This supports the progressive neurodegenerative visual phenotype resulting from Stargardt disease pathophysiology.


MAXO:0000950

[PMID:18541085] [SUPPORT] Stargardt's patients respond well to magnification. Simple bifocal glasses may be used in the early stages. Visual rehabilitation can help Stargardt's patients to learn independence in their activities of daily living. --- Explanation: This clinical rehabilitation study supports low-vision aids and visual rehabilitation as beneficial supportive care in Stargardt disease.


MAXO:0000950

[PMID:18541085] [INDIRECT EVIDENCE] [SUPPORT] Stargardt's patients respond well to magnification. Simple bifocal glasses may be used in the early stages. Visual rehabilitation can help Stargardt's patients to learn independence in their activities of daily living. --- Explanation: This clinical rehabilitation study supports low-vision aids and visual rehabilitation as beneficial supportive care in Stargardt disease.


MAXO:0000950


MAXO:0000079

[PMID:33369172] [SUPPORT] Our study highlights the essential role of the subspecialty field of ocular genetics in obtaining accurate diagnoses for the delivery of correct counseling and interventional trial eligibility assessment. --- Explanation: This clinical genetics series supports genetic counseling as an important component of Stargardt disease care.


MAXO:0001001

[PMID:37834872] [SUPPORT] In gene therapy, dual adeno-associated virus and non-viral vectors have been successful in delivering the human ABCA4 gene in preclinical studies. --- Explanation: This review summarizes preclinical success of dual-vector and non-viral ABCA4 delivery strategies.

[PMID:37940365] [SUPPORT] the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6.8 kb ABCA4 open reading frame --- Explanation: This review highlights the translational effort to replace the full ABCA4 coding sequence.


MAXO:0000058

[PMID:37834872] [SUPPORT] For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years. --- Explanation: This review summarizes promising phase 2 trial data for ALK-001 as a visual cycle-modulating strategy.


MAXO:0000016

[PMID:37834872] [SUPPORT] Stem cell therapy using human pluripotent stem cell-derived retinal pigment epithelium cells demonstrated long-term safety three years after implantation and visual acuity improvements in the first two years after initiation of therapy. --- Explanation: This review reports early safety and signal of benefit from stem cell-derived RPE transplantation in Stargardt disease.


MAXO:0000058

[PMID:38837708] [SUPPORT] Drug-mediated re-acidification of lysosomes in the RPE of STGD1 restores CatD functional activity and reduces the accumulation of immature CatD protein loads. --- Explanation: Patient-derived RPE models support lysosomal re-acidification as a plausible mechanistically targeted intervention.


MAXO:0000058

[clinicaltrials:NCT03364153] [SUPPORT] The purpose of this study is to evaluate the safety and efficacy of avacincaptad pegol intravitreal injection compared to Sham in participants with autosomal recessive Stargardt disease 1 (STGD1). --- Explanation: This completed phase IIb trial supports complement inhibition as a clinically investigated therapeutic strategy in Stargardt disease.


hgnc:34

[PMID:9054934] [SUPPORT] This gene, ABCR, is expressed exclusively and at high levels in the retina, in rod but not cone photoreceptors, as detected by in situ hybridization. Mutational analysis of ABCR in STGD families revealed a total of 19 different mutations including homozygous mutations in two families with consanguineous parentage. These data indicate that ABCR is the causal gene of STGD/FFM. --- Explanation: This landmark study established ABCA4 as the causal gene for Stargardt disease.

[PMID:37940365] [SUPPORT] STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). --- Explanation: This review confirms ABCA4 as the major causative gene in autosomal recessive STGD1.


hgnc:14415

[PMID:15557430] [SUPPORT] In a European family with adSTGD-like MD, a novel ELOVL4 mutation was found to underlie the disorder. --- Explanation: This family study supports ELOVL4 as a causal gene for autosomal dominant Stargardt-like macular dystrophy.


hgnc:9454

[PMID:29416601] [SUPPORT] We found a novel heterozygous missense mutation, c.734T>C (p.L245P) in the PROM1 gene. --- Explanation: This multigenerational family study supports PROM1 as a causative gene in Stargardt4-like macular dystrophy.


MONDO:0019353

[PMID:9054934] [SUPPORT] Stargardt disease (STGD, also known as fundus flavimaculatus; FFM) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material. --- Explanation: This landmark genetic paper directly supports autosomal recessive inheritance for classic ABCA4-related Stargardt disease.


MONDO:0018229

[PMID:29188475] [SUPPORT] The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of < 10%, TEN is defined as skin involvement of > 30%, and SJS/TEN overlap as 10-30% skin involvement. --- Explanation: Lerch et al. (2018) define SJS by its extent of skin detachment (<10% BSA), directly establishing epidermal detachment as the cardinal diagnostic criterion and phenotypic feature.

[PMID:34577817] [SUPPORT] Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare diseases that are characterized by widespread epidermal necrosis and sloughing of skin. --- Explanation: Frantz et al. (2021) characterize SJS/TEN by epidermal necrosis and sloughing, confirming skin detachment as the pathognomonic clinical finding.


MONDO:0018229

[PMID:29188475] [SUPPORT] SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. --- Explanation: Lerch et al. (2018) describe oral mucous membrane involvement as a hallmark of SJS/TEN, confirming oral mucosal erosions as a universal clinical feature.


MONDO:0018229

[PMID:29188475] [SUPPORT] SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. --- Explanation: Lerch et al. (2018) describe genital mucous membrane involvement as part of the characteristic mucocutaneous presentation of SJS/TEN.


MONDO:0018229

[PMID:29188475] [SUPPORT] SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions --- Explanation: Lerch et al. (2018) explicitly describe fever as part of the influenza-like prodromal phase preceding skin lesions, confirming fever as a consistent early phenotypic feature.


MONDO:0018229

[PMID:29188475] [SUPPORT] In SJS/TEN, the most common complications are ocular, cutaneous, or renal. --- Explanation: Lerch et al. (2018) identify ocular complications as the most common complications of SJS/TEN, supporting conjunctivitis and ocular involvement as a major phenotypic feature.


MONDO:0018229

[PMID:29188475] [SUPPORT] Pulmonary and hepatic involvement is frequent. --- Explanation: Lerch et al. (2018) note that pulmonary involvement is frequent in SJS/TEN, supporting respiratory complications as a recognized phenotypic feature.


MONDO:0018229

[PMID:29188475] [SUPPORT] SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. --- Explanation: Lerch et al. (2018) describe the influenza-like prodrome featuring malaise as universal in SJS/TEN, preceding the characteristic skin and mucous membrane lesions.


MONDO:0018229

[PMID:29188475] [SUPPORT] SJS/TEN manifest with an "influenza-like" prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. --- Explanation: Lerch et al. (2018) describe cutaneous lesions in SJS/TEN as explicitly painful, directly supporting skin pain as a cardinal symptom of the acute disease.


MONDO:0018229

[PMID:29188475] [SUPPORT] In SJS/TEN, the most common complications are ocular, cutaneous, or renal. --- Explanation: Lerch et al. (2018) explicitly identify renal complications among the most common manifestations of SJS/TEN, supporting renal insufficiency as a recognized phenotypic feature requiring monitoring.


MONDO:0018229

[PMID:29188475] [SUPPORT] Pulmonary and hepatic involvement is frequent. --- Explanation: Lerch et al. (2018) explicitly state that hepatic involvement is frequent in SJS/TEN, supporting it as a recognized phenotypic complication.


MONDO:0018229

[PMID:15536433] [INDIRECT EVIDENCE] [SUPPORT] Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. --- Explanation: Nassif et al. (2004) directly demonstrated that drug-specific CD8+ CTLs are the effector cells in TEN/SJS, killing autologous keratinocytes in a drug-dependent manner via perforin/granzyme pathways.

[PMID:22322005] [INDIRECT EVIDENCE] [SUPPORT] The endogenous peptide-loaded HLA-B∗1502 molecule presented CBZ to CTLs without the involvement of intracellular drug metabolism or antigen processing. --- Explanation: Wei and Chung (2012) elucidated the molecular mechanism of HLA-B*15:02-mediated carbamazepine presentation, showing direct drug interaction with HLA bypassing conventional antigen processing — explaining why this reaction affects genetically susceptible individuals independent of drug metabolism.


MONDO:0018229


MONDO:0018229

[PMID:19029983] [INDIRECT EVIDENCE] [SUPPORT] Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. --- Explanation: Chung et al. (2008) demonstrated that granulysin is the dominant cytotoxic mediator in SJS/TEN blister fluid, far exceeding other cytotoxic molecules, and that its depletion reduces cytotoxicity — directly establishing it as the key effector molecule.

[PMID:19029983] [INDIRECT EVIDENCE] [SUPPORT] blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule --- Explanation: Chung et al. (2008) showed that CTLs and NK cells are the dominant blister cells and granulysin is the most highly expressed cytotoxic molecule, identifying the cellular and molecular effectors.


MONDO:0018229

[PMID:12707034] [INDIRECT EVIDENCE] [SUPPORT] Taken together, these results indicate that sFasL secreted by PBMCs, not keratinocytes, plays a crucial role in the apoptosis and pathomechanism of TEN and SJS, and that the serum sFasL level may be a good indicator for the early diagnosis of TEN and SJS. --- Explanation: Abe et al. (2003) demonstrated that soluble FasL secreted by PBMCs (not keratinocytes) drives keratinocyte apoptosis, with high sFasL levels in SJS and TEN patients versus controls — establishing Fas–FasL as an independent apoptotic pathway from granulysin.


MONDO:0018229

[PMID:29793265] [INDIRECT EVIDENCE] [SUPPORT] In the case of carbamazepine-induced SJS/TEN, the tight association of the HLA-B*1502 allele (sensitivity 100%, specificity 97% and odds ratio 2504) provides a plausible basis for further development of such a test to identify individuals at risk of developing this life-threatening condition. --- Explanation: Hung, Chung and Chen (2005) demonstrated that HLA-B*1502 has near-perfect sensitivity and specificity for carbamazepine-induced SJS/TEN in Asian populations, establishing the basis for pharmacogenomic screening.

[PMID:22541332] [INDIRECT EVIDENCE] [SUPPORT] The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). --- Explanation: Chung and Hung (2012) review confirms the HLA allele associations for both carbamazepine (HLA-B*15:02) and allopurinol (HLA-B*58:01) as genetic determinants of SJS/TEN susceptibility.


MONDO:0018229

[PMID:15536433] [INDIRECT EVIDENCE] [SUPPORT] These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN. --- Explanation: Nassif et al. (2004) demonstrated that drug-specific perforin/granzyme B-mediated cytotoxicity is an independent killing modality in SJS/TEN, complementing granulysin as an effector mechanism.

[PMID:22541332] [INDIRECT EVIDENCE] [SUPPORT] Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. --- Explanation: Chung and Hung (2012) describe the hierarchy of cytotoxic mechanisms in SJS/TEN, placing perforin/granzyme B alongside granulysin as an effector of epidermal necrosis.


MAXO:0000950

[PMID:34577817] [SUPPORT] Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare diseases that are characterized by widespread epidermal necrosis and sloughing of skin. They are associated with significant morbidity and mortality, and early diagnosis and treatment is critical in achieving favorable outcomes for patients. --- Explanation: Frantz et al. (2021) emphasize that early diagnosis and treatment — including specialized supportive care — is critical for favorable outcomes in SJS/TEN.


MAXO:0000058

[PMID:34577817] [SUPPORT] cyclosporine is the most effective therapy for the treatment of SJS, and a combination of intravenous immunoglobulin (IVIg) and corticosteroids is most effective for SJS/TEN overlap and TEN. --- Explanation: Frantz et al. (2021) identify cyclosporine as the most effective treatment specifically for SJS, distinguishing its role from IVIG+corticosteroids for TEN and SJS/TEN overlap.

[PMID:29188475] [SUPPORT] The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A. --- Explanation: Lerch et al. (2018) confirm cyclosporine A as one of the most frequently used treatments for SJS/TEN in clinical practice.


MAXO:0000058

[PMID:34577817] [PARTIAL] a combination of intravenous immunoglobulin (IVIg) and corticosteroids is most effective for SJS/TEN overlap and TEN. Due to the rare nature of the disease, there is a lack of prospective, randomized controlled trials and conducting these in the future would provide valuable insights into the management of this disease. --- Explanation: Frantz et al. (2021) support IVIG use primarily for SJS/TEN overlap and TEN rather than isolated SJS, and acknowledge the lack of RCT-level evidence — hence the PARTIAL support rating.


MAXO:0000058

[PMID:29188475] [PARTIAL] The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A. --- Explanation: Lerch et al. (2018) confirm systemic corticosteroids as one of the most frequently used treatments for SJS/TEN in clinical practice. However, evidence of benefit is not definitive, hence PARTIAL support; they are widely used but remain controversial.


HGNC.SYMBOL:HLA-B*15:02 Allele

[PMID:29793265] [SUPPORT] In the case of carbamazepine-induced SJS/TEN, the tight association of the HLA-B*1502 allele (sensitivity 100%, specificity 97% and odds ratio 2504) provides a plausible basis for further development of such a test to identify individuals at risk of developing this life-threatening condition. --- Explanation: Hung et al. (2005) established the extraordinary strength of the HLA-B*1502 association with carbamazepine-induced SJS/TEN, providing the evidence basis for pharmacogenomic screening guidelines.


HGNC.SYMBOL:HLA-B*58:01 Allele

[PMID:22541332] [SUPPORT] The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). --- Explanation: Chung and Hung (2012) confirm HLA-B*58:01 as a key genetic risk factor for allopurinol-induced SJS/TEN, alongside HLA-B*15:02 for carbamazepine.


MONDO:0007160

[PMID:11007540] [SUPPORT] Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital "membranous" anomaly of the vitreous of all affected individuals.
 --- Explanation: Establishes that the membranous vitreous phenotype is characteristic of all individuals with COL2A1 haploinsufficiency mutations.

[PMID:20179744] [SUPPORT] Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01).
 --- Explanation: Vitreous anomalies are significantly associated with confirmed COL2A1 mutations in STL1 patients.


MONDO:0007160


MONDO:0007160

[PMID:17675240] [SUPPORT] Of 111 patients who had no prophylactic retinopexy (group 1; mean age, 49 years), 73% (81/111) suffered RD and 48% (53/111) were bilateral.
 --- Explanation: Large cohort study of 204 STL1 patients demonstrates the extremely high (73%) retinal detachment rate in untreated patients.

[PMID:20462780] [SUPPORT] The ocular abnormalities include severe myopia, abnormalities of the vitreous, and a high risk of retinal detachment (60% of cases), which may cause blindness (4% of cases).
 --- Explanation: Review confirms the high retinal detachment risk in Stickler syndrome.


MONDO:0007160

[PMID:23110709] [SUPPORT] Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%).
 --- Explanation: Systematic review of 313 Stickler syndrome patients confirms high prevalence of sensorineural hearing loss.

[PMID:23110709] [SUPPORT] Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).
 --- Explanation: While hearing loss is less frequent in STL1 (COL2A1) than other types, over half of STL1 patients have hearing impairment.


MONDO:0007160

[PMID:20462780] [SUPPORT] Osteoarthritis (75% of patients) with onset before 30 years of age is a severe manifestation that causes chronic hip and low back pain and functional impairments. Joint replacement surgery is often required.
 --- Explanation: Review documents high prevalence of early-onset osteoarthritis in Stickler syndrome, with 75% of patients affected before age 30.


MONDO:0007160

[PMID:20179744] [INDIRECT EVIDENCE] [SUPPORT] Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay.
 --- Explanation: Large-scale genotype-phenotype study of 100 STL1 patients confirms that the majority of COL2A1 mutations cause haploinsufficiency through NMD.

[PMID:11007540] [INDIRECT EVIDENCE] [SUPPORT] Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding.
 --- Explanation: Study examining vitreous phenotypes confirms that premature termination codons causing haploinsufficiency are the predominant mutation type in STL1.


MONDO:0007160

[PMID:11007540] [INDIRECT EVIDENCE] [SUPPORT] Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital "membranous" anomaly of the vitreous of all affected individuals.
 --- Explanation: Demonstrates that COL2A1 haploinsufficiency produces the characteristic membranous vitreous phenotype that is pathognomonic for STL1.

[PMID:11007540] [INDIRECT EVIDENCE] [SUPPORT] Experience has shown that vitreous slit-lamp biomicroscopy can distinguish between patients with COL2A1 mutations and those with dominant negative mutations in COL11A1, who produce a different "beaded" vitreous phenotype.
 --- Explanation: The membranous vitreous phenotype can be used to distinguish STL1 (COL2A1) from STL2 (COL11A1), supporting its diagnostic utility.


MAXO:0000004

[PMID:17675240] [SUPPORT] Of 62 patients who had bilateral prophylactic cryotherapy (group 2; mean age, 21 years), 8% (5/62) suffered failure of prophylaxis. There were no cases of bilateral detachments. The mean follow-up period was 11.5 years.
 --- Explanation: Large retrospective study demonstrates prophylactic cryotherapy reduces retinal detachment from 73% to 8% in STL1 patients.

[PMID:17675240] [SUPPORT] Prophylactic cryotherapy substantially reduces the risk of RD in type 1 Stickler syndrome and, in this series, eliminated the risk of bilateral detachments.
 --- Explanation: Study conclusion confirms effectiveness of prophylactic treatment.


MAXO:0000011


MAXO:0000004


HGNC.SYMBOL:COL2A1 Mutations


MONDO:0008491

[PMID:11756577] [SUPPORT] Stiff-person syndrome is a disabling central nervous system disorder with no satisfactory treatment that is characterized by muscle rigidity, episodic muscle spasms, high titers of antibodies against glutamic acid decarboxylase (GAD65) --- Explanation: The randomized controlled trial establishes muscle rigidity as a defining characteristic of the syndrome.


MONDO:0008491

[PMID:11756577] [SUPPORT] Stiff-person syndrome is a disabling central nervous system disorder with no satisfactory treatment that is characterized by muscle rigidity, episodic muscle spasms --- Explanation: Episodic muscle spasms are a core diagnostic feature of the syndrome.

[PMID:3281011] [SUPPORT] Stiff-man syndrome is a rare disorder of the central nervous system consisting of progressive, fluctuating muscle rigidity with painful spasms --- Explanation: The original description establishes painful spasms as a core feature.

[PMID:37059468] [SUPPORT] episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression --- Explanation: The 2023 review confirms episodic painful muscle spasms as a key clinical manifestation requiring treatment.


MONDO:0008491

[PMID:35084720] [NO_EVIDENCE] In spite of the unique clinical phenotype that each of these disorders has, there is significant overlapping symptomatology characterized by autoimmune neuronal excitability --- Explanation: Neuronal hyperexcitability underlies the exaggerated startle response as part of the SPS phenotype.


MONDO:0008491

[PMID:11756577] [PARTIAL] Eleven patients who received immune globulin became able to walk more easily or without assistance --- Explanation: The improvement in walking ability after treatment indicates gait disturbance is a significant feature of the disease.


MONDO:0008491

[PMID:37059468] [NO_EVIDENCE] stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms --- Explanation: Truncal muscle stiffness leads to the characteristic lumbar hyperlordosis posture in SPS patients.


MONDO:0008491

[PMID:37059468] [NO_EVIDENCE] stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms --- Explanation: Gait dysfunction and sudden muscle spasms predispose SPS patients to frequent falls.


MONDO:0008491

[PMID:37059468] [NO_EVIDENCE] the challenges in distinguishing the conditioning effects or expectations of chronically applied therapies from objective meaningful clinical benefits --- Explanation: Task-specific phobias and anxiety are recognized clinical features complicating assessment of treatment effects in SPS.


MONDO:0008491

[PMID:3281011] [INDIRECT EVIDENCE] [SUPPORT] A band comigrating with glutamic acid decarboxylase in sodium dodecyl sulfate-polyacrylamide gels appeared to be the only nervous-tissue antigen recognized by cerebrospinal fluid antibodies --- Explanation: This landmark paper identified GAD as the target antigen in stiff person syndrome, establishing the autoimmune basis.

[PMID:35084720] [INDIRECT EVIDENCE] [SUPPORT] Very high serum anti-GAD antibody titers are a key diagnostic feature for all GAD-SD, commonly associated with the presence of GAD antibodies in the CSF, a reduced CSF GABA level --- Explanation: High GAD antibody titers correlate with reduced GABA levels, supporting the pathophysiological mechanism.

[PMID:37059468] [INDIRECT EVIDENCE] [PARTIAL] caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis --- Explanation: The 2023 review confirms that intrathecal GAD antibody synthesis and impaired GABAergic neurotransmission are central to pathogenesis.


MONDO:0008491


MONDO:0008491

[PMID:35084720] [INDIRECT EVIDENCE] [SUPPORT] the phenomenon of reciprocal inhibition as the fundamental mechanism of the patients' muscle stiffness and spasms --- Explanation: Directly describes the loss of reciprocal inhibition mechanism.


MONDO:0008491

[PMID:35084720] [INDIRECT EVIDENCE] [PARTIAL] Very high serum anti-GAD antibody titers are a key diagnostic feature for all GAD-SD, commonly associated with the presence of GAD antibodies in the CSF, a reduced CSF GABA level and increased anti-GAD-specific IgG intrathecal synthesis denoting stimulation of B-cell clones in the CNS --- Explanation: Describes the intrathecal B-cell activation and antibody synthesis characteristic of SPS.

[PMID:37059468] [INDIRECT EVIDENCE] [PARTIAL] caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis --- Explanation: Confirms that intrathecal GAD antibody synthesis is central to the autoimmune pathogenesis.


MAXO:0000058

[PMID:35084720] [PARTIAL] details on symptomatic GABA-enhancing drugs and the currently available immunotherapies in a step-by-step approach --- Explanation: Benzodiazepines are established as first-line symptomatic GABA-enhancing therapy.


MAXO:0000058

[PMID:37059468] [PARTIAL] combination therapies with the preferred gamma-aminobutyric acid-enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin --- Explanation: Baclofen is listed as a preferred GABA-enhancing antispasmodic drug for symptomatic treatment of SPS.


CHEBI:2972

[PMID:37059468] [INDIRECT EVIDENCE] [PARTIAL] combination therapies with the preferred gamma-aminobutyric acid-enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin --- Explanation: Baclofen is listed as a preferred GABA-enhancing antispasmodic drug for symptomatic treatment of SPS.


MAXO:0000058

[PMID:11756577] [SUPPORT] Among patients who received immune globulin first, stiffness scores decreased significantly (P=0.02) --- Explanation: Randomized controlled trial demonstrated significant efficacy of IVIg.

[PMID:11756577] [SUPPORT] Intravenous immune globulin is a well-tolerated and effective, albeit costly, therapy for patients with stiff-person syndrome and anti-GAD65 antibodies. --- Explanation: The trial conclusion establishes IVIg as effective treatment.

[PMID:37059468] [PARTIAL] detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab --- Explanation: The 2023 review confirms IVIg as a key immunotherapy option in the treatment algorithm.


MAXO:0000058

[PMID:37059468] [PARTIAL] detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab --- Explanation: Rituximab is included as part of the current immunotherapy options for SPS treatment.

[PMID:35084720] [PARTIAL] focuses on therapies providing details on symptomatic GABA-enhancing drugs and the currently available immunotherapies in a step-by-step approach --- Explanation: Rituximab is part of the step-by-step therapeutic approach for refractory cases.


HGNC.SYMBOL:HLA-DRB1

[PMID:35084720] [NO_EVIDENCE] In spite of the unique clinical phenotype that each of these disorders has, there is significant overlapping symptomatology characterized by autoimmune neuronal excitability --- Explanation: The shared autoimmune basis across GAD-spectrum disorders implies common genetic susceptibility factors including HLA associations.


MONDO:0013034

[PMID:9887343] [SUPPORT] Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. --- Explanation: Describes the striate keratoderma pattern.

[PMID:9887343] [SUPPORT] Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. --- Explanation: Documents the ultrastructural skin pathology.


MONDO:0013034

[PMID:9887343] [INDIRECT EVIDENCE] [SUPPORT] The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-terminal region of the peptide. --- Explanation: Identifies the first DSP mutation causing striate PPK through haploinsufficiency.

[PMID:9887343] [INDIRECT EVIDENCE] [SUPPORT] This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity. --- Explanation: Establishes DSP haploinsufficiency as a novel disease mechanism.


MONDO:0013034


MAXO:0000058


MAXO:0000079


hgnc:3052

[PMID:9887343] [SUPPORT] The disorder mapped to chromosome 6p21 with a maximum lod score of 10.67. --- Explanation: Linkage mapping confirming DSP locus for striate PPK.


MONDO:0010434


MONDO:0010434

[PMID:32092619] [INDIRECT EVIDENCE] [PARTIAL] SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas. --- Explanation: Supports the presence of SS18-SSX fusions as a defining feature of synovial sarcoma.


MAXO:0000004


MAXO:0000014


MAXO:0000647


CHEBI:5864


CHEBI:28748


HGNC.SYMBOL:SS18-SSX Fusion

[PMID:15208645] [PARTIAL] The t(X;18)(p11.2;q11.2) is the cytogenetic hallmark of synovial sarcoma and is present in more than 90% of the cases. --- Explanation: Abstract notes t(X;18) as the cytogenetic hallmark of synovial sarcoma.


MONDO:0010434

[PMID:9930576] [SUPPORT] Synovial sarcoma is a rare soft tissue tumor of children and adults that is --- Explanation: Abstract describes synovial sarcoma as a rare soft tissue tumor.


MONDO:0007915

[PMID:23846232] [PARTIAL] The most common clinical manifestations were malar rash (61.3%)... --- Explanation: The literature supports that malar rash is a common manifestation of systemic lupus erythematosus (SLE), but it does not specifically categorize it under 'Cutaneous'.

[PMID:16966017] [PARTIAL] There are 3 forms of cutaneous lupus: chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. --- Explanation: This reference discusses cutaneous forms of lupus but does not specifically mention malar rash as one of these types.

[PMID:17711886] [PARTIAL] The common symptoms of SLE in children and adolescents include... rash... --- Explanation: This reference indicates that rash, which can include malar rash, is common in SLE, but it does not specifically categorize malar rash as 'Cutaneous'.


MONDO:0007915

[PMID:15379880] [SUPPORT] Photosensitivity is one the most common manifestations of lupus erythematosus. --- Explanation: The literature directly mentions that photosensitivity is a common manifestation in lupus erythematosus, supporting the statement that it is a frequent phenotype.

[PMID:31909888] [PARTIAL] Fatigue, widespread pain, sleep dysfunction, and mood disorders are common symptoms in SLE. --- Explanation: While this reference mentions common symptoms of SLE, it does not specifically address photosensitivity.

[PMID:30988213] [PARTIAL] The cutaneous manifestations of lupus erythematosus (LE) include LE-specific and LE-nonspecific skin lesions. --- Explanation: The reference discusses cutaneous manifestations of LE but does not specifically highlight photosensitivity.

[PMID:31575058] [PARTIAL] The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors. --- Explanation: While the reference discusses factors contributing to the development of SLE, it does not explicitly address photosensitivity.

[PMID:23846232] [PARTIAL] The most common clinical manifestations were malar rash (61.3%), arthritis (52.3%), haematological disease (51.6%), oral ulcers (51%) and renal disease (40.6%). --- Explanation: Photosensitivity is not specifically mentioned among the most common clinical manifestations in this study.

[PMID:29087262] [PARTIAL] Analysis revealed that photosensitivity, nephritis and thrombocytopenia were negatively associated with familial SLE. --- Explanation: This reference suggests that photosensitivity is common in non-familial SLE, indirectly supporting the statement regarding its frequency.


MONDO:0007915

[PMID:19591780] [SUPPORT] Arthritis in systemic lupus erythematosus (SLE) is one of the most common disease manifestations. Nearly all joints can be affected by SLE, but hand and knee involvement are the most typical. --- Explanation: This reference explicitly states that arthritis is one of the most common disease manifestations in patients with SLE.

[PMID:27742023] [PARTIAL] The precise nature of the disorder can be obscure and different disorders can present with similar symptoms, such as joint pain. --- Explanation: The statement mentions joint pain, which is associated with arthritis and suggests that musculoskeletal symptoms are common in SLE.

[PMID:19013374] [SUPPORT] Systemic lupus erythematosus is an autoimmune and inflammatory disease characterized by a variety of symptoms, including arthropathy. The clinical presentation of joint involvement varies, ranging from arthralgia without erosions or deformity to an erosive arthropathy and severe functional disability. --- Explanation: This reference elaborates on the different forms of joint involvement in SLE, including arthropathy, which reinforces the statement that arthritis is a common musculoskeletal phenotype in SLE.

[PMID:32956154] [PARTIAL] Polyautoimmunity was recorded in 15 patients with RA (13.8%), 43 with SLE (41%), and 2 controls (2.2%). ... In SLE, joint damage (OR, 2.282; p = 0.038) and anti-RNP antibodies (OR, 5.095; p = 0.028) were risk factors for polyautoimmunity... --- Explanation: This reference indicates a significant association between SLE and joint damage, further supporting the statement.


MONDO:0007915

[PMID:16530602] [SUPPORT] Lupus nephritis is one of the more serious manifestations of the systemic autoimmune disease, systemic lupus erythematosus, and is associated with considerable morbidity and even mortality. --- Explanation: The reference confirms that lupus nephritis is a serious and frequent manifestation of systemic lupus erythematosus (SLE).

[PMID:32295853] [SUPPORT] The frequency of endstage renal disease (ESRD) from systemic lupus erythematosus (SLE) in the United States has not improved over the last few decades in large population datasets. --- Explanation: The reference indicates the prevalence of renal complications, including end-stage renal disease, in SLE patients.

[PMID:35775489] [SUPPORT] Lupus nephritis (LN) is common in people with systemic lupus erythematosus (SLE) and advances, almost invariably, to end-stage renal disease (ESRD). --- Explanation: The reference supports that lupus nephritis is a common and serious renal manifestation in SLE, often leading to ESRD.

[PMID:22192934] [SUPPORT] Renal involvement is frequent (20 to 50% of cases) during the course of systemic lupus erythematosus (SLE). --- Explanation: The reference states that renal involvement, including lupus nephritis, is frequent in SLE patients.


MONDO:0007915

[PMID:26170228] [SUPPORT] The prevalence of leukopenia is reported in 22-41.8% of cases. --- Explanation: The study reports that leukopenia is prevalent in 22-41.8% of SLE cases, indicating that leukopenia is a frequent hematologic abnormality in SLE patients.

[PMID:27590999] [PARTIAL] TCP was the most prevalent hematological abnormality evident in 15%, more than leucopenia (14%) and anemia (2%). --- Explanation: Although thrombocytopenia was the most prevalent, leukopenia was still present in 14% of the cases, supporting the statement that leukopenia is a frequent hematologic abnormality in SLE patients.

[PMID:8130682] [PARTIAL] The increased risk of infection in patients with SLE is due in part to changes in the white blood cells though treatments do not yet aim to modify these. --- Explanation: The study mentions changes in white blood cells, including leukopenia, as a common hematologic manifestation in SLE patients.

[PMID:15580984] [SUPPORT] In the updated 1982 ACR criteria, the presence of one or more of the four elements: 1) hemolytic anemia (with reticulocytosis); 2) leukopenia (<4000/microL on two or more occasions)... is now considered as a single hematologic disorder. --- Explanation: The ACR criteria include leukopenia as a significant hematologic disorder in the diagnosis of SLE, supporting its frequent occurrence.


MONDO:0007915

[PMID:32896257] [PARTIAL] Thrombocytopenia was classified as mild (100-149x109/L), moderate (31-99x109/L) or severe (</=30x109/L platelets). --- Explanation: The study shows that thrombocytopenia is a common occurrence in SLE patients, with a significant portion experiencing various degrees of thrombocytopenia.

[PMID:12481500] [SUPPORT] Thrombocytopenia is common, autoimmune and associated with a decreased survival. --- Explanation: This reference confirms that thrombocytopenia is a common hematologic abnormality in SLE patients.

[PMID:15580984] [SUPPORT] Thrombocytopenia (< 100,000/microL in the absence of offending drugs) is now considered as a single hematologic disorder. --- Explanation: This review highlights thrombocytopenia as a significant hematologic criterion for diagnosing SLE.


MONDO:0007915

[PMID:12481500] [NO_EVIDENCE] Anaemia is the most common hematological abnormality in SLE, it is multifactorial. The most common form of anaemia is that of chronic disease, and it is relate with inflammatory cytokines. Other tips of anaemia are: iron deficiency anaemia, autoimmune haemolytic anaemia, pure red cell aplasia. --- Explanation: The abstract mentions that autoimmune hemolytic anemia is one of the types of anemia in SLE but does not provide information about its frequency.

[PMID:36469203] [PARTIAL] Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that would potentiate many pathological complications, including hemolytic anemia. --- Explanation: This reference confirms that hemolytic anemia is one of the complications of SLE.

[PMID:15580984] [PARTIAL] In the updated 1982 ACR criteria, the presence of one or more of the four elements: 1) hemolytic anemia (with reticulocytosis)... is now considered as a single hematologic disorder. --- Explanation: The ACR criteria for diagnosing SLE includes hemolytic anemia as one of the hematologic disorders.

[PMID:30631001] [PARTIAL] One month prior, she had been diagnosed with Evans syndrome (haemolytic anemia with positive Coombs test and thrombocytopenia)... Further examination revealed positive for ANA, anti-SSA, and diagnosis of SLE was established. --- Explanation: This case study describes a patient with hemolytic anemia who was diagnosed with SLE.


MONDO:0007915

[PMID:16218467] [REFUTE] Pericarditis is the most common cardiac abnormality in systemic lupus erythematosus (SLE) patients... --- Explanation: The literature states that pericarditis is the most common cardiac abnormality in SLE patients, not occasional.

[PMID:31507126] [REFUTE] Several diseases are frequently associated with such manifestations. They include systemic lupus erythematosus... --- Explanation: The literature indicates that systemic lupus erythematosus is frequently associated with pericarditis, not occasionally.

[PMID:33216192] [REFUTE] Pericarditis can be present in the context of systemic inflammatory rheumatic diseases... --- Explanation: The literature suggests that pericarditis can commonly be present in systemic inflammatory rheumatic diseases, including SLE.


MONDO:0007915

[PMID:8153398] [PARTIAL] The pleuropulmonary manifestation of systemic lupus erythematous (SLE) are pleuritis, acute lupus pneumonitis, chronic interstitial lung disease with fibrosis, alveolar hemorrhage, respiratory muscle and diaphragmatic dysfunction, atelectasis, bronchiolitis obliterans, pulmonary vascular disease with pulmonary hypertension, and pulmonary embolism. --- Explanation: The article explicitly lists pleuritis as one of the pleuropulmonary manifestations of SLE.

[PMID:25318967] [PARTIAL] We investigated the clinical characteristics of pleural effusion in systemic lupus erythematosus (SLE). A prospective analysis of 17 SLE patients with pleural effusion (seven lupus pleuritis, eight transudative effusions and two parapneumonic effusions) was performed. --- Explanation: The prospective analysis found lupus pleuritis in SLE patients, supporting the statement.

[PMID:12055395] [PARTIAL] Fortunately, pleuritis in systemic lupus erythematosus is not usually as life threatening as may be the renal or central nervous system complications. Nevertheless, pleuritis does occur in systemic lupus erythematosus and may be a significant cause of morbidity. --- Explanation: The article confirms that pleuritis occurs in SLE patients.


MONDO:0007915

[PMID:33626435] [PARTIAL] The prevalence of explicit episodes of seizures among SLE patients, varies from 2 to 8%. --- Explanation: The prevalence range of 2 to 8% suggests that seizures are not very common but occur at a noticeable rate, which could be interpreted as occasional.

[PMID:12136236] [PARTIAL] Seizures and psychosis are neuropsychiatric (NP) manifestations of a large number of systemic lupus erythematosus (SLE) patients. --- Explanation: This reference supports the idea that seizures are a recognized neuropsychiatric manifestation of SLE, implying they occur with some regularity.


MONDO:0007915

[PMID:30375754] [PARTIAL] Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. --- Explanation: The study indicates that psychosis is an infrequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), which suggests it is not common but does occur occasionally. This partially supports the statement that psychosis is an 'occasional' manifestation.

[PMID:37771217] [PARTIAL] Psychosis is a rare NPSLE manifestation that can occur at any phase of the illness; 21% of SLE-related psychosis cases occur at the onset of SLE. --- Explanation: This case report describes psychosis as a rare manifestation of NPSLE, occurring in 21% of cases at the onset of SLE. While 'rare' and 'occasional' are not identical, they both imply infrequency, partially supporting the statement.


MONDO:0007915

[PMID:27709413] [INDIRECT EVIDENCE] [PARTIAL] Here, we review what is known on the altered metabolic patterns of CD4(+) T cells, B cells, and myeloid cells in lupus patients and lupus-prone mice and how they contribute to lupus pathogenesis. --- Explanation: The reference discusses the altered metabolic patterns of B cells, CD4(+) T cells, and myeloid cells (which include macrophages) and their contribution to lupus, which indirectly supports the involvement of these cell types in lupus mechanisms, but it does not specifically address immune complex formation directly.

[PMID:29925508] [INDIRECT EVIDENCE] [PARTIAL] TLR4(+)CXCR4(+) plasma cells drive nephritis development in systemic lupus erythematosus. --- Explanation: This reference demonstrates the role of specific plasma cells in the development of lupus nephritis, implying their role in immune complex-related pathology, but does not detail the direct involvement of B cells or macrophages in immune complex formation.

[PMID:34402453] [INDIRECT EVIDENCE] [PARTIAL] B-lymphocytes are crucial in the pathogenesis of systemic lupus erythematosus (SLE), including autoantibody production, antigen presentation, co-stimulation, and cytokine secretion. --- Explanation: The reference highlights the crucial role of B cells in the pathogenesis of SLE through mechanisms such as autoantibody production, which is critical for immune complex formation. However, it does not explicitly discuss the role of plasma cells or macrophages in the context given.

[PMID:22999705] [INDIRECT EVIDENCE] [PARTIAL] C1q opsonized apoptotic cells also exert an immunosuppressive effect through cytokine regulation and the stimulation of additional opsonins by macrophages. --- Explanation: This suggests that macrophages have a role in immune complex-mediated processes through cytokine regulation and opsonin stimulation, contributing to the immune system’s activity in lupus but does not detail the involvement of B cells or plasma cells in immune complex formation.


MONDO:0007915


MONDO:0007915

[PMID:33841392] [INDIRECT EVIDENCE] [SUPPORT] Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease characterized by tissue damage and widespread inflammation in response to environmental challenges. Deposition of immune complexes in kidneys glomeruli are associated with lupus nephritis, determining SLE diagnosis. --- Explanation: The literature supports the deposition of immune complexes in kidney glomeruli but does not cover skeletal joints, skin, heart, or lung in this context.

[PMID:30009962] [INDIRECT EVIDENCE] [SUPPORT] LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. --- Explanation: This confirms immune complex deposition in kidneys.


MONDO:0007915

[PMID:35872103] [INDIRECT EVIDENCE] [SUPPORT] The autoantibodies, especially anti-dsDNA and anti-Sm autoantibodies are highly specific to SLE, and participate in the immune complex formation and inflammatory damage on multiple end-organs such as kidney, skin, and central nervous system (CNS). --- Explanation: This paper directly establishes that autoantibodies form immune complexes which cause inflammatory damage to multiple organs in SLE.

[PMID:16572034] [INDIRECT EVIDENCE] [SUPPORT] Systemic lupus erythematosus is an autoimmune disease that causes inflammation in the tissues of the brain, endothelial cells, gastrointestinal/genitourinary (GI/GU), joints, kidneys, muscles, and skin. Lupus comprises a range of multisystem disorders involving the deposition of aberrant immune complexes into tissues. --- Explanation: The literature confirms the deposition of immune complexes in kidneys, joints, and skin, but does not mention the heart and lung specifically in this context.


MONDO:0007915

[PMID:2860699] [INDIRECT EVIDENCE] [NO_EVIDENCE] Evidence is now slowly accumulating that substantiates that immune complex deposition, complement activation and subsequent inflammatory reaction is responsible for the majority of the cardiovascular manifestations of SLE, for example, pericarditis, myocarditis, endocarditis, coronary arteritis, coronary atherosclerosis, and systemic and pulmonary vasculitis. --- Explanation: This confirms immune complex deposition in the heart.

[PMID:28900675] [INDIRECT EVIDENCE] [NO_EVIDENCE] Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE --- Explanation: This reference does not mention the deposition of immune complexes in skeletal joints.

[PMID:158982] [INDIRECT EVIDENCE] [NO_EVIDENCE] Abundant evidence currently exists to suggest that immune complexes play an important role in inflammatory diseases of the lung. ... systemic lupus erythematosus have been shown to be associated with the presence of immune complexes both in lung and in the serum. --- Explanation: This confirms immune complex deposition in the lung.


MONDO:0007915

[PMID:24834763] [INDIRECT EVIDENCE] [SUPPORT] An increased expression of type I IFN-regulated genes, termed IFN signature, has been reported in patients with SLE. --- Explanation: This review describes the type I interferon gene signature in SLE, supporting chronic activation of the type I interferon pathway.


MAXO:0000058

[PMID:28130918] [SUPPORT] Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE --- Explanation: This phase IIb trial demonstrated that anifrolumab significantly reduced SLE disease activity, with greater efficacy in patients with high interferon gene signatures.


NCIT:C166658

[PMID:28130918] [INDIRECT EVIDENCE] [SUPPORT] Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate-to-severe SLE --- Explanation: This phase IIb trial demonstrated that anifrolumab significantly reduced SLE disease activity, with greater efficacy in patients with high interferon gene signatures.


MAXO:0000058


MAXO:0000058

[PMID:22127708] [SUPPORT] Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE --- Explanation: This phase III BLISS-76 trial demonstrated that belimumab significantly improved SLE outcomes compared to placebo.


NCIT:C91385

[PMID:22127708] [INDIRECT EVIDENCE] [SUPPORT] Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE --- Explanation: This phase III BLISS-76 trial demonstrated that belimumab significantly improved SLE outcomes compared to placebo.


MAXO:0000950


HGNC.SYMBOL:HLA-DR2

[PMID:37801591] [PARTIAL] HLA-DR2 patients had an earlier onset of disease as well as a higher prevalence of oral ulcer, avascular necrosis of bone, and renal involvement (lupus nephritis) --- Explanation: The study indicates that HLA-DR2 is associated with an increased susceptibility to SLE in the Taiwanese population.


HGNC.SYMBOL:HLA-DR3

[PMID:17910142] [PARTIAL] A positive HLA-DR3 anti-Ro/La antibody association was found in the patients with SLE (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). --- Explanation: The study finds a significant association between HLA-DR3 and the presence of anti-Ro/La antibodies in SLE patients, though it does not establish that HLA-DR3 alone is a genetic risk factor for SLE.

[PMID:6103441] [NO_EVIDENCE] It was also noted that the distribution of DR antigens in the hydralazine-SLE patients was significantly different from that in the group with idiopathic SLE. --- Explanation: This study highlights differences in HLA-DR distribution between drug-induced SLE and idiopathic SLE, but it does not specifically address the genetic contribution of HLA-DR3 to idiopathic SLE.


HGNC.SYMBOL:PTPN22

[PMID:31232672] [SUPPORT] We found that the PTPN22 polymorphisms rs1310182 A allele (p = 0.01, OR = 1.92 95% CI = 1.16-3.18), and rs1310182 AA genotype with (p < 0.001) and rs12760457 TT (p = 0.046) were associated with PSLE. --- Explanation: The study indicates that certain polymorphisms in the PTPN22 gene are associated with pediatric systemic lupus erythematosus (PSLE), supporting the genetic association between PTPN22 and SLE.


HGNC.SYMBOL:STAT4

[PMID:23912645] [SUPPORT] Our results showed a significant association between rs7574865 T allele (odds ratio (OR) = 1.50, 95 % CI = 1.18-1.92, P = 0.002) and susceptibility to SLE. --- Explanation: The study found a significant association between the STAT4 gene (specifically rs7574865) and susceptibility to SLE.

[PMID:31082500] [SUPPORT] Analysis of existing transcriptomes and GWAS data identified eight up-regulated candidate genes with more than four relationships among the different pathways associated with SNPs to pinpoint the relevant loci linked to SLE... STAT4... --- Explanation: This study identified STAT4 as one of the candidate genes associated with SLE through transcriptomic data analysis and pathway analysis of GWAS data.

[PMID:34525002] [NO_EVIDENCE] The main objective of this study was to evaluate an association between HLA, STAT4, IRF5, and BLK polymorphisms and the presence of JA in Brazilian individuals with SLE. METHODS: Patients were selected from a cohort of individuals with SLE followed at 2 rheumatology reference centers in Salvador, Bahia, Brazil. --- Explanation: The study aimed to evaluate the association between STAT4 polymorphisms and the presence of Jaccoud Arthropathy in individuals with SLE, implying an association between STAT4 and SLE.


HGNC.SYMBOL:IRF5

[PMID:20962850] [SUPPORT] Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5)... This study confirms the existence of multiple genetic risk factors for SLE... --- Explanation: The study clearly identifies IRF5 as one of the genetic risk factors associated with SLE.

[PMID:26233721] [SUPPORT] This meta-analysis demonstrated the IRF5 rs2070197 polymorphism conferred susceptibility to SLE in all subjects... The IRF5 rs2070197 polymorphism was identified as risk factors for SLE... --- Explanation: The meta-analysis confirms the association of IRF5 polymorphism with SLE in multiple populations.

[PMID:23251221] [SUPPORT] Interferon regulatory factor 5 (IRF5) is a transcription factor which... genetic variants of IRF5 have been strongly linked to SLE pathogenesis. --- Explanation: The paper discusses the role of IRF5 in SLE pathogenesis and confirms its genetic association with the disease.

[PMID:20453440] [SUPPORT] Recent large-scale studies in the Caucasian populations identified many new susceptibility genes to systemic lupus erythematosus (SLE)... In IRF5, the risk haplotype in Caucasians was not present in Japanese... All of these genes were associated with SLE... --- Explanation: The study confirms that IRF5 is associated with SLE in both Caucasian and Japanese populations.

[PMID:36245280] [SUPPORT] IRF5 plays a crucial role in the development of lupus... Genome-wide association studies have identified several systemic lupus erythematosus (SLE) risk single-nucleotide polymorphisms (SNPs) enriched in the IRF5 locus. --- Explanation: The study identifies IRF5 as playing a key role in SLE development with confirmed risk SNPs.


HGNC.SYMBOL:TLR7


HGNC.SYMBOL:TLR9


HGNC.SYMBOL:MYD88


HGNC.SYMBOL:CYBB


HGNC.SYMBOL:TNFSF13B


HGNC.SYMBOL:IL21


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:STAT3


HGNC.SYMBOL:IL10


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:IRF8


HGNC.SYMBOL:IKZF1


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:REL


HGNC.SYMBOL:PRDM1


ECTO:0000006

[PMID:24763542] [SUPPORT] While it is known that UV radiation exposure may exacerbate pre-existing lupus, it remains unclear whether UV exposure is a risk factor for the development of SLE. --- Explanation: The literature clearly states that UV radiation exposure may exacerbate pre-existing lupus, which supports the statement.

[PMID:22385883] [SUPPORT] Exposure to sunlight is one of the environmental factors involved in the pathogenesis of systemic lupus erythematosus. --- Explanation: The study investigates the seasonal variation in lupus flares and correlates increased flares with increased temperature and sunshine, supporting the statement that UV exposure exacerbates disease activity.


ECTO:3000000

[PMID:36332998] [PARTIAL] This review focuses on SLE risk potentially associated with environmental factors including infections. --- Explanation: The paper identifies infections as one of the environmental factors potentially associated with the risk of SLE, thereby supporting the statement that infections can trigger or worsen disease symptoms in SLE.

[PMID:25022358] [SUPPORT] New mechanisms for autoimmunity triggered by Epstein-Barr virus and human commensal microbiota have been described. --- Explanation: This review mentions infections, specifically Epstein-Barr virus, as triggers for autoimmunity, which supports the notion that infections can influence SLE disease activity.

[PMID:38146370] [PARTIAL] The relationship between Systemic lupus erythematosus (SLE) and Epstein-Barr virus (EBV) infection has been suggested for decades, but the underlying mechanism of the EBV influence on SLE development remains to be elucidated. --- Explanation: This study supports the connection between infections (specifically EBV) and SLE, further establishing that infections can trigger or worsen SLE symptoms.


MONDO:0005100


MONDO:0005100

[PMID:38927538] [INDIRECT EVIDENCE] [SUPPORT] In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. --- Explanation: This evidence supports the early vascular injury mechanism by demonstrating that defective angiogenesis and capillary abnormalities precede fibrosis in SSc.

[PMID:38927538] [INDIRECT EVIDENCE] [SUPPORT] Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. --- Explanation: This describes multiple mechanisms of endothelial dysfunction in SSc, including impaired angiogenesis, endothelial-to-mesenchymal transition, and inflammatory mediator release that contribute to vascular pathology.


MONDO:0005100

[PMID:38296975] [INDIRECT EVIDENCE] [PARTIAL] Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. --- Explanation: This genetic evidence implicates B cell and Fc receptor biology in SSc susceptibility, with IRF8 being a key regulator of immune cell development and interferon responses that contribute to immune dysregulation.

[PMID:38296975] [INDIRECT EVIDENCE] [PARTIAL] Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. --- Explanation: This supports the role of B cell biology and autoantibody production in SSc pathogenesis, demonstrating that B cell-specific genetic variants contribute to disease risk.


MONDO:0005100

[PMID:38147960] [INDIRECT EVIDENCE] [PARTIAL] SSc skin demonstrated an increased abundance of COMP+, COL11A1+, MYOC+, CCL19+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblasts signatures and decreased proportions of CXCL12+ and PI16+ fibroblast signatures in the Prospective Registry of Early Systemic Sclerosis and Genetics versus Environment in Scleroderma Outcome Study cohorts. --- Explanation: This demonstrates the heterogeneity of fibroblast populations in SSc, with increased profibrotic fibroblast subpopulations and decreased normal fibroblast signatures contributing to excessive ECM deposition.

[PMID:38147960] [INDIRECT EVIDENCE] [PARTIAL] The proportions of profibrotic COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ and proinflammatory CCL19+ fibroblast signatures were positively correlated with clinical and histopathological parameters of skin fibrosis, whereas signatures of CXCL12+ and PI16+ fibroblasts were inversely correlated. --- Explanation: This provides direct evidence linking specific fibroblast subpopulations to clinical severity of skin fibrosis, supporting the role of fibroblast activation in SSc pathogenesis and disease progression.


HGNC.SYMBOL:HLA-DRB1


HGNC.SYMBOL:IRF5


HGNC.SYMBOL:STAT4


MONDO:0010711

[PMID:36944446] [PARTIAL] TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome is a rare X-linked disorder affecting the RBM10 gene --- Explanation: Lane et al. 2023 case report documents atrial septal defect as a cardinal feature of TARP syndrome caused by RBM10 splice mutations.


MONDO:0010711

[PMID:36944446] [PARTIAL] At birth, he had an ASD and Robin sequence, two of the eponymous features --- Explanation: Lane et al. 2023 confirms Robin sequence (including micrognathia) as a defining feature of TARP syndrome.


MONDO:0010711

[PMID:36944446] [PARTIAL] At birth, he had an ASD and Robin sequence, two of the eponymous features --- Explanation: Lane et al. 2023 documents cleft palate as part of the Robin sequence phenotype in TARP syndrome.


MONDO:0010711

[PMID:36944446] [PARTIAL] TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome --- Explanation: Lane et al. 2023 identifies talipes equinovarus (clubfoot) as the eponymous first feature of TARP syndrome.


MONDO:0010711

[PMID:36944446] [PARTIAL] At birth, he had an ASD and Robin sequence, two of the eponymous features --- Explanation: Lane et al. 2023 documents Robin sequence (which includes glossoptosis - posterior tongue displacement) as an eponymous feature of TARP syndrome.


MONDO:0010711

[PMID:37340830] [SUPPORT] Vitelline vascular remnants (VVR) are a rare vitelline duct anomaly with approximately 26 cases previously reported. There are no previously reported cases of VVRs in patients with TARP syndrome. --- Explanation: Omorodion et al. 2023 documents the first reported case of vitelline vascular remnant causing intestinal obstruction in a TARP syndrome patient, expanding the known phenotypic spectrum.


MONDO:0010711

[PMID:34031074] [PARTIAL] intrauterine growth restriction, with a persistent left superior vena cava, interatrial communication and a horseshoe kidney --- Explanation: Manotas et al. 2021 documents a TARP syndrome patient with horseshoe kidney, a previously unreported renal manifestation in this syndrome.


MONDO:0010711

[PMID:34031074] [PARTIAL] Additionally, postnatal optic nerve atrophy was diagnosed. --- Explanation: Manotas et al. 2021 documents postnatal optic nerve atrophy in a TARP syndrome patient, expanding the known systemic manifestations of this condition.


MONDO:0010711

[PMID:30462380] [PARTIAL] He was diagnosed with severe to profound intellectual disability in early childhood and had not developed language at age 28 years. --- Explanation: Højland et al. 2018 documents severe to profound intellectual disability in the first reported adult TARP patient, confirming this as a consistent and persistent feature.


MONDO:0010711

[PMID:30462380] [PARTIAL] Clinical examination of the patient revealed sloping forehead, prominent nasal bridge and nose, high myopia, esotropia, displacement of lacrimal points in the cranial direction --- Explanation: Højland et al. 2018 documents esotropia as an ophthalmic finding in an adult TARP patient, expanding the known ocular manifestations of the syndrome.


MONDO:0010711

[PMID:30462380] [PARTIAL] Surgery for severe thoracolumbar scoliosis was performed at age 21 years. --- Explanation: Højland et al. 2018 documents severe thoracolumbar scoliosis in an adult TARP patient, a previously unreported manifestation of TARP syndrome.


MONDO:0010711

[PMID:30462380] [PARTIAL] Clinical examination of the patient revealed sloping forehead, prominent nasal bridge and nose, high myopia, esotropia --- Explanation: Højland et al. 2018 documents prominent nose and nasal bridge as craniofacial features in an adult TARP patient, expanding the phenotypic spectrum beyond the initially described cardinal features.


MONDO:0010711

[PMID:36944446] [INDIRECT EVIDENCE] [PARTIAL] TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome is a rare X-linked disorder affecting the RBM10 gene --- Explanation: Lane et al. 2023 establishes RBM10 as the causative gene for TARP syndrome with loss-of-function splice mutations.


MONDO:0010711


MONDO:0010711

[PMID:39080280] [INDIRECT EVIDENCE] [PARTIAL] RBM10 serves as an anchor for recruiting Histone Deacetylase 1 (HDAC1) to facilitate H4K16 deacetylation and R-loop homeostasis to maintain replication fork stability --- Explanation: Machour et al. 2024 demonstrates the splicing-independent role of RBM10 in maintaining DNA replication fork stability through HDAC1 recruitment.


MAXO:0000004

[PMID:36944446] [PARTIAL] At birth, he had an ASD and Robin sequence, two of the eponymous features --- Explanation: Lane et al. 2023 case report of a TARP patient with ASD requiring cardiac management for survival beyond neonatal period.


MAXO:0000004

[PMID:36944446] [PARTIAL] TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome --- Explanation: Lane et al. 2023 documents Robin sequence (which includes cleft palate) as a defining feature of TARP, requiring surgical intervention for airway management and feeding.


MAXO:0000004

[PMID:36944446] [PARTIAL] TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome --- Explanation: Lane et al. 2023 case report of TARP patient with talipes equinovarus, which typically requires orthopedic surgical intervention.


MAXO:0000950

[PMID:36944446] [PARTIAL] our patient's survival past the neonatal period --- Explanation: Lane et al. 2023 demonstrates that coordinated multidisciplinary management of TARP syndrome features enables survival beyond the historically fatal neonatal period.


HGNC.SYMBOL:RBM10

[PMID:36944446] [SUPPORT] a previously unreported splicing mutation c.2295+1G>A in the RBM10 gene --- Explanation: Lane et al. 2023 documents RBM10 splice-site mutations as causative for TARP syndrome.


HGNC.SYMBOL:NUMB


HGNC.SYMBOL:VCL


HGNC.SYMBOL:CD44


HGNC.SYMBOL:TNC


MONDO:0000764

[PMID:25284770] [SUPPORT] Corneal dystrophies are a group of inherited disorders localized to various layers of the cornea that affect corneal transparency and visual acuity. --- Explanation: Corneal opacity is the defining feature of all TGFBI dystrophies.


MONDO:0000764


MONDO:0000764

[PMID:25284770] [INDIRECT EVIDENCE] [SUPPORT] The gene product, transforming growth factor β induced protein (TGFBIp) accumulates as insoluble deposits in various forms. The severity, clinicopathogenic variations, age of the onset, and location of the deposits depend on the type of amino acid alterations in the protein. --- Explanation: Comprehensive review establishing the mechanism of TGFBIp deposition and genotype-phenotype correlation.

[PMID:11501939] [INDIRECT EVIDENCE] [SUPPORT] The codons R124 and R555 of the TGFBI gene were hotspots in Japanese patients --- Explanation: Establishes R124 and R555 as mutational hotspots with clear genotype-phenotype correlation.


MONDO:0000764

[PMID:25284770] [INDIRECT EVIDENCE] [SUPPORT] The deposition of insoluble protein materials in the form of extracellular deposits or intracellular cysts is pathognomic. --- Explanation: Confirms that insoluble protein deposition in the cornea is the pathognomonic feature of TGFBI dystrophies.


MONDO:0000764

[PMID:25284770] [INDIRECT EVIDENCE] [SUPPORT] There is no effective treatment to prevent, halt, or reverse the deposition of TGFBIp. --- Explanation: Confirms lack of disease-modifying treatments and progressive nature of corneal opacification.


MAXO:0010039


MAXO:0000004


MAXO:0000079


hgnc:11771

[PMID:30760895] [SUPPORT] To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described. --- Explanation: Comprehensive mutation survey establishing 70+ pathogenic TGFBI variants.

[PMID:30760895] [SUPPORT] an increase to the worldwide detection rate in all populations from 75 to 90% could be achieved by the addition of six mutations --- Explanation: The 5 hotspot mutations account for 75% of cases; 11 mutations cover 90%.

[PMID:11501939] [SUPPORT] These studies showed a clear genotype/phenotype correlation associated with the TGFBI gene. --- Explanation: Confirms clear genotype-phenotype correlations across populations.


MONDO:1040001

[PMID:20556892] [SUPPORT] Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities) --- Explanation: GeneReviews describes ectodermal dysplasia as a core feature.


MONDO:1040001

[PMID:20556892] [SUPPORT] Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. --- Explanation: GeneReviews lists cleft lip/palate as a core feature of the TP63-related disorder spectrum.


MONDO:1040001

[PMID:20556892] [SUPPORT] Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. --- Explanation: GeneReviews lists split-hand/foot malformation/syndactyly as a core feature of the TP63-related disorder spectrum.


MONDO:1040001

[PMID:20556892] [SUPPORT] ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids) --- Explanation: Ankyloblepharon is specific to the AEC subtype.


MONDO:1040001

[PMID:20556892] [SUPPORT] skin erosions especially on the scalp associated with areas of scarring, and alopecia --- Explanation: Scalp skin erosions are an AEC-specific feature. HP:0200042 (Skin ulcer) is the closest available HPO term for erosions.


MONDO:1040001

[PMID:20556892] [SUPPORT] skin erosions especially on the scalp associated with areas of scarring, and alopecia --- Explanation: Scarring alopecia is an AEC-specific feature.


MONDO:1040001


MONDO:1040001

[PMID:12070241] [INDIRECT EVIDENCE] [SUPPORT] The pattern of heterozygous mutations is distinct for each of these syndromes. The functional effects on the p63 proteins also vary between syndromes. --- Explanation: Establishes that different TP63 mutation patterns cause distinct syndromes within the spectrum.

[PMID:12070241] [INDIRECT EVIDENCE] [SUPPORT] In all of these syndromes, the mutation appears to have both dominant negative and gain of function effects rather than causing a simple loss of function. --- Explanation: Clarifies that TP63 mutations act through dominant negative/GOF rather than haploinsufficiency.

[PMID:19676060] [INDIRECT EVIDENCE] [SUPPORT] AEC and RHS mutations in the 5' and 3' ends of the p63 gene point towards a critical role of the DeltaNp63alpha isoform for the AEC/RHS phenotype. --- Explanation: Identifies the DeltaNp63alpha isoform as key to AEC/Rapp-Hodgkin.


MONDO:1040001

[PMID:20556892] [INDIRECT EVIDENCE] [SUPPORT] Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection, and infants with severe skin erosions are monitored and treated aggressively for dehydration, electrolyte imbalances, malnutrition, and infection. --- Explanation: GeneReviews describes severe neonatal skin erosions requiring aggressive management.


MAXO:0000950

[PMID:20556892] [SUPPORT] A multidisciplinary team of specialists in clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology is recommended. --- Explanation: GeneReviews management guidance.


MAXO:0000950

[PMID:20556892] [SUPPORT] Skin erosions are treated with gentle wound care and periodic, dilute bleach soaks to prevent secondary infection --- Explanation: GeneReviews skin erosion management.


MAXO:0000950


MAXO:0000079

[PMID:20556892] [SUPPORT] Once the TP63 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. --- Explanation: GeneReviews genetic counseling guidance.


hgnc:15979

[PMID:12070241] [SUPPORT] Several autosomal dominantly inherited human syndromes have recently been shown to result from mutations in the p63 gene. --- Explanation: Establishes TP63 mutations as causative for the syndrome family.

[PMID:20556892] [SUPPORT] The proportion of individuals with a TP63-related disorder caused by a de novo TP63 pathogenic variant is approximately 70%. --- Explanation: GeneReviews confirms high de novo rate.

[PMID:19676060] [SUPPORT] Eight were missense mutations within the coding region of the SAM domain. Three other mutations were located in exon 14 sequences, which encode the TI domain. --- Explanation: Characterizes mutation clustering in SAM/TI domains for AEC/RHS.


MONDO:0015484

[PMID:12932389] [SUPPORT] This disease is one of the main causes of epileptic seizures in many less developed countries --- Explanation: Neurocysticercosis is a major cause of seizures in endemic regions.


MAXO:0000058

[PMID:12932389] [SUPPORT] Available therapeutic measures include steroids, treatments for symptoms, surgery, and, more controversially, antiparasitic drugs to kill brain parasites. --- Explanation: The abstract lists antiparasitic drugs among available treatments.


MAXO:0000004

[PMID:12932389] [SUPPORT] Available therapeutic measures include steroids, treatments for symptoms, surgery, and, more controversially, antiparasitic drugs to kill brain parasites. --- Explanation: The abstract includes surgery as a treatment option.


NCBITaxon:6204

[PMID:12932389] [SUPPORT] The larval stage of the pork tapeworm (Taenia solium) infects the human nervous system, causing neurocysticercosis. --- Explanation: The abstract identifies Taenia solium as the causative tapeworm.


MONDO:0017991


MONDO:0017991

[PMID:29191819] [PARTIAL] The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms. --- Explanation: Vascular signs and ischemic symptoms (from arterial stenosis) are part of the relapse definition, confirming their centrality in TAK.


MONDO:0017991

[PMID:29191819] [INDIRECT EVIDENCE] [PARTIAL] To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). --- Explanation: The TAKT study targets IL-6 receptor signaling, confirming the central role of IL-6 in TAK pathogenesis.


MAXO:0000058

[PMID:29191819] [SUPPORT] Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. --- Explanation: The TAKT study used glucocorticoids to induce remission in all patients before randomization, confirming their role as standard first-line therapy.