MONDO:0009693

[PMID:25439696] [INDIRECT EVIDENCE] [SUPPORT] existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). --- Explanation: Anemia is a defining CRAB feature of myeloma, resulting from bone marrow failure due to plasma cell infiltration.


MONDO:0009693


MONDO:0009693

[PMID:34201396] [INDIRECT EVIDENCE] [SUPPORT] Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. --- Explanation: The review confirms immunoparesis as a key feature of myeloma leading to increased infection risk.


MONDO:0009693

[PMID:25439696] [INDIRECT EVIDENCE] [SUPPORT] attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). --- Explanation: Renal failure is a defining CRAB feature of myeloma in the IMWG diagnostic criteria.


MAXO:0000058

[PMID:18753647] [SUPPORT] Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. --- Explanation: The VISTA trial demonstrated superiority of bortezomib-based therapy in newly diagnosed myeloma, establishing proteasome inhibitors as backbone agents.


MAXO:0000058

[PMID:18032763] [SUPPORT] Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in patients with relapsed or refractory multiple myeloma. --- Explanation: The MM-009 trial demonstrated superiority of lenalidomide plus dexamethasone over dexamethasone alone in relapsed myeloma.


MAXO:0000058

[PMID:31141632] [SUPPORT] the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. --- Explanation: The MAIA trial demonstrated that adding daratumumab to lenalidomide-dexamethasone significantly reduced disease progression or death in newly diagnosed myeloma.


MAXO:0010039

[PMID:12736280] [SUPPORT] High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age. --- Explanation: The MRC Myeloma VII trial established high-dose therapy with autologous stem-cell rescue as an effective first-line treatment for transplant-eligible myeloma patients.


MAXO:0000058

[PMID:33626253] [SUPPORT] Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. --- Explanation: The KarMMa trial demonstrated that idecabtagene vicleucel induced responses in 73% of heavily pretreated relapsed/refractory myeloma patients.


MAXO:0000058

[PMID:35661166] [SUPPORT] Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. --- Explanation: The MajesTEC-1 trial demonstrated a 63% overall response rate with teclistamab in triple-class-exposed relapsed/refractory myeloma.


hgnc:5477

[PMID:25439696] [SUPPORT] These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. --- Explanation: The IMWG criteria include cytogenetic abnormalities such as t(4;14) and t(14;16) as myeloma-defining events, reflecting the central role of IGH translocations.


hgnc:11998


HGNC.SYMBOL:Hyperdiploidy


MONDO:0005301

[PMID:23897142] [NO_EVIDENCE] Acute muscle weakness, a common disorder in pediatrics, can occur from impairment of any part of the motor unit, including the upper motor neuron, lower motor neuron, peripheral nerve, neuromuscular junction or muscle. --- Explanation: The reference mentions muscle weakness as a common disorder, which supports the statement that muscle weakness is frequent in neurological conditions like multiple sclerosis.

[PMID:32120056] [NO_EVIDENCE] Spasticity is the velocity-dependent hypertonia frequently encountered in patients affected by Upper Motor Neuron Syndrome. --- Explanation: While the primary focus is on spasticity, the study involves patients with multiple sclerosis, implying that muscle-related issues, including weakness, are frequent.

[PMID:26863109] [PARTIAL] Hip mROM was extremely sensitive in measuring lower limb motor impairment, being correlated with muscle strength and also altered in patients without clinically detectable disability. --- Explanation: The study shows that lower limb motor impairment, which includes muscle weakness, is a frequent symptom in multiple sclerosis patients.

[PMID:15228757] [PARTIAL] Cross-sectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. --- Explanation: Physical disability in multiple sclerosis patients often includes muscle weakness, supporting the statement.

[PMID:10101582] [NO_EVIDENCE] Chief among these symptoms, both in relation to their frequency and their impact on the patient, are spasticity, ataxia and fatigue. --- Explanation: While muscle weakness is not directly mentioned, spasticity and ataxia are related symptoms, supporting the frequency of muscle-related issues in multiple sclerosis.


MONDO:0005301

[PMID:3355400] [SUPPORT] Fatigue is a frequent symptom in multiple sclerosis (MS) that can interfere with a patient's daily functioning. --- Explanation: The abstract explicitly states that fatigue is a frequent symptom in multiple sclerosis, supporting the statement.

[PMID:26195047] [PARTIAL] The relation of fatigue in multiple sclerosis (MS) to the visual system, an emerging structural and functional surrogate in MS, has not been well established. --- Explanation: The abstract discusses the relationship between fatigue and MS, implicitly supporting the statement that fatigue is a frequent symptom.


MONDO:0005301

[PMID:22721362] [PARTIAL] Spasticity in multiple sclerosis --- Explanation: The title of the article directly mentions spasticity in the context of multiple sclerosis.

[PMID:35977131] [NO_EVIDENCE] Symptoms of MS depend on the areas of neuronal involvement. Common symptoms include sensory disturbances, motor weakness, impaired gait, incoordination, optic neuritis, and Lhermitte sign. --- Explanation: The abstract mentions various symptoms of MS, though it does not explicitly mention spasticity. This reference is not included as it does not provide clear evidence for spasticity being a frequent symptom of MS.

[PMID:30286958] [PARTIAL] The most common causes leading to spasticity include stroke, traumatic brain injury, multiple sclerosis, spinal cord injury, and cerebral palsy. --- Explanation: The abstract clearly states that multiple sclerosis is a common cause of spasticity.

[PMID:32120056] [PARTIAL] Spasticity is the velocity-dependent hypertonia frequently encountered in patients affected by Upper Motor Neuron Syndrome. --- Explanation: The abstract discusses spasticity in the context of multiple sclerosis, indicating it is a frequent symptom.

[PMID:10101582] [SUPPORT] Chief among these symptoms, both in relation to their frequency and their impact on the patient, are spasticity, ataxia and fatigue. --- Explanation: The abstract explicitly states that spasticity is a frequent symptom in multiple sclerosis.

[PMID:22612755] [SUPPORT] Spasticity is one of the most common symptoms. --- Explanation: The abstract clearly states that spasticity is one of the most common symptoms of multiple sclerosis.

[PMID:20586738] [PARTIAL] Spasticity is a sign of upper motor neurone lesion, which can be located in the cerebrum or the spinal cord, and be caused by stroke, multiple sclerosis, spinal cord injury, brain injury, cerebral paresis, or other neurological conditions. --- Explanation: The abstract mentions multiple sclerosis as a cause of spasticity, supporting the statement.

[PMID:26611270] [PARTIAL] Individuals with multiple sclerosis (MS) spasticity present a wide range of symptoms and disability levels that are frequently challenging to manage. --- Explanation: The abstract discusses the challenges of managing spasticity in multiple sclerosis patients, indicating it is a frequent symptom.

[PMID:30626509] [PARTIAL] Spasticity in patients with multiple sclerosis can be debilitating and detrimental to the function and quality of life of patients. --- Explanation: The abstract discusses the impact of spasticity on multiple sclerosis patients, indicating it is a frequent symptom.


MONDO:0005301

[PMID:37379870] [SUPPORT] Multiple sclerosis causes motor, sensory, cerebellar, and autonomic dysfunctions, as well as cognitive and psychoemotional impairment. The most frequently compromised cognitive domains are complex attention/information processing, memory, executive and visuospatial functions. --- Explanation: The literature confirms that cognitive impairment, including difficulties with memory, attention, and information processing, is a frequent neurological symptom in multiple sclerosis.

[PMID:27207446] [SUPPORT] Information processing speed (IPS) is a prevalent cognitive impairment in multiple sclerosis (MS). --- Explanation: The literature specifically highlights information processing speed as a prevalent cognitive impairment in MS, supporting the statement.

[PMID:37031630] [SUPPORT] Cognitive impairment is a core symptom of multiple sclerosis, leading to disability in 40-70% of patients. The most common cognitive domains affected by MS are information processing speed, complex attention, executive functions and less frequently, episodic declarative memory. --- Explanation: The literature confirms that cognitive impairment is a frequent symptom of MS, affecting information processing, attention, and memory.


MONDO:0005301


MONDO:0005301

[PMID:24507511] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is considered a prototype inflammatory autoimmune disorder of the central nervous system (CNS)... These autoreactive lymphocytes can migrate to the CNS where they become reactivated upon encountering their target antigen, initiating an autoimmune inflammatory attack. This ultimately leads to demyelination and axonal damage. --- Explanation: The literature supports that MS involves the immune system attacking myelin in the CNS, leading to demyelination. It specifically mentions the role of autoreactive lymphocytes, which include T and B lymphocytes.

[PMID:19847447] [INDIRECT EVIDENCE] [PARTIAL] Oligodendrocytes are the myelinating cells of the central nervous system (CNS)... we will lay out the different pathways leading to oligodendrocyte and myelin loss in human CNS diseases... --- Explanation: The literature supports the involvement of oligodendrocytes in myelination and their loss in CNS diseases like MS, which leads to demyelination.

[PMID:36889543] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease... CNS myelin is normally produced by oligodendroglial cells. --- Explanation: The literature supports that MS is a demyelinating disease affecting the CNS, with oligodendrocytes being the cells responsible for myelin production.

[PMID:37629092] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin... However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. --- Explanation: The literature supports that MS involves demyelination and neurodegeneration in the CNS, with oligodendrocytes playing a crucial role in this process.

[PMID:15727225] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is characterized by multiple demyelinated inflammatory lesions disseminated in the central nervous system (CNS)... different mechanisms of demyelination, such as T-cell/macrophage-mediated demyelination, antibody/complement-mediated demyelination, and primary damage of the oligodendrocyte have been observed in individual MS patients. --- Explanation: The literature supports that MS involves demyelination in the CNS and mentions the role of T-cells and oligodendrocytes in this process.

[PMID:21425268] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology... Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes... --- Explanation: The literature supports that MS is an autoimmune disease causing demyelination in the CNS, involving oligodendrocytes.

[PMID:28674983] [INDIRECT EVIDENCE] [SUPPORT] MS is a chronic inflammatory disease of the central nervous system caused by aberrant immune activation resulting in damage to myelin sheaths within the brain and spinal cord and axonal loss --- Explanation: The literature supports that MS involves immune activation leading to damage of myelin sheaths in the CNS.

[PMID:17548563] [INDIRECT EVIDENCE] [SUPPORT] Substantial evidence supports autoimmune activity as the etiologic mechanism underlying multiple sclerosis (MS)... Both the innate and the adaptive arms of the immune system are involved in the aberrant response to several antigens associated with the myelin sheath and oligodendrocytes (OGCs)... --- Explanation: The literature supports that MS is an autoimmune disease involving the immune system's attack on myelin and oligodendrocytes in the CNS.

[PMID:24507514] [INDIRECT EVIDENCE] [SUPPORT] This review, focused on demyelination in multiple sclerosis, is divided in two parts. The first part addresses the many and not exclusive mechanisms leading to demyelination in the central nervous system... the influence of a primary immune response against myelin antigen(s), with a diversity of potential targets. --- Explanation: The literature supports that MS involves immune responses against myelin antigens leading to demyelination in the CNS.


MONDO:0005301

[PMID:32801039] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where immunopathology is thought to be mediated by myelin-reactive CD4+ T helper (TH) cells. The TH cells most commonly implicated in the pathogenesis of the disease are of TH1 and TH17 lineage, which are defined by the production of interferon-γ and interleukin-17, respectively. --- Explanation: Directly establishes TH1 and TH17 cells as the key drivers of MS immunopathology.

[PMID:21338381] [INDIRECT EVIDENCE] [SUPPORT] Multiple sclerosis (MS) is an autoimmune disease characterized by recurrent episodes of demyelination and axonal lesion mediated by CD4(+) T cells with a proinflammatory Th1 and Th17 phenotype, macrophages, and soluble inflammatory mediators. --- Explanation: Confirms Th1 and Th17 phenotypes as mediators of MS demyelination and axonal damage.

[PMID:21338381] [INDIRECT EVIDENCE] [SUPPORT] Autoreactive Th17 cells can migrate through the BBB by the production of cytokines such as IL-17 and IL-22, which disrupt tight junction proteins in the central nervous system (CNS) endothelial cells. --- Explanation: Describes the mechanism by which Th17 cells cross the BBB via IL-17 and IL-22 disruption of tight junctions.


MONDO:0005301

[PMID:21550344] [INDIRECT EVIDENCE] [SUPPORT] Leukocyte entry into the CNS is nonetheless an early event in multiple sclerosis (MS), an inflammatory disorder of the CNS... Immune cells of MS subjects express inflammatory cytokines, reactive oxygen species (ROS) and enzymes that can facilitate their migration to the CNS by influencing BBB function, either directly or indirectly. --- Explanation: This reference supports the statement that immune cells cross the blood-brain barrier and create inflammation in the central nervous system.

[PMID:34440810] [INDIRECT EVIDENCE] [SUPPORT] During this early stage of the disease, leukocytes cross the blood-brain barrier to drive the formation of focal demyelinating plaques. --- Explanation: This reference directly supports the statement by mentioning that leukocytes cross the blood-brain barrier and drive the formation of focal demyelinating plaques, which are inflammatory lesions.

[PMID:30407467] [INDIRECT EVIDENCE] [SUPPORT] Neuroinflammation is triggered when peripheral leukocytes migrate to the central nervous system and release cytokines such as interleukins 1 and 6 (IL-1 and 6) and tumor necrosis factor (TNF), which act on dwelling cells. --- Explanation: This reference supports the statement by explaining that peripheral leukocytes migrate to the CNS and trigger neuroinflammation.

[PMID:29515568] [INDIRECT EVIDENCE] [SUPPORT] Astrocytes are now recognized to be early and highly active players during lesion formation and key for providing peripheral immune cells access to the central nervous system. --- Explanation: This reference supports the statement by mentioning the role of astrocytes in providing access for peripheral immune cells to the CNS, contributing to lesion formation.


MAXO:0000058

[PMID:12894379] [SUPPORT] In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. --- Explanation: The reference confirms the efficacy of interferon beta and glatiramer acetate in treating RRMS, which aligns with the statement about DMTs reducing the frequency and severity of relapses.

[PMID:24494618] [SUPPORT] Diseasemodifying drugs (DMDs) that reduce the frequency of relapses, development of brain lesions, and progression of disability are the standard of care for relapsing forms of MS, and the use of DMDs should be initiated as early as possible --- Explanation: The reference supports the statement by indicating that DMDs reduce the frequency of relapses and progression of disability in MS.

[PMID:29921609] [PARTIAL] Those using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS. --- Explanation: The reference supports the statement by highlighting the beneficial effects of fingolimod and natalizumab on patients' work life, indirectly supporting their role in reducing the severity of relapses.

[PMID:27549763] [PARTIAL] Disease modifying therapies (DMTs) approved for relapsing multiple sclerosis interfere with a variety of immunological mechanisms to reduce rates of relapse, accumulation of disease burden measured by magnetic resonance imaging (MRI), and decline in neurological function over the two to three year duration of typical randomized controlled trials. --- Explanation: The reference supports the statement regarding the reduction of relapse rates and disease burden but notes that the benefits on long-term disability reduction are less clear.

[PMID:32560364] [PARTIAL] Several FDA-approved medications seek to alleviate disease progression by reducing the impact of such factors as demyelination and neurodegeneration. --- Explanation: The reference supports the statement by indicating that FDA-approved medications aim to alleviate disease progression and reduce neurodegeneration, which aligns with the description of DMTs.


MAXO:0000950

[PMID:9817541] [SUPPORT] Management of symptoms, however, can help everyone with the disease. Several new therapies, including tizanidine, intrathecal baclofen, botulinum toxin injections, gabapentin, ondansitron, thalamic stimulation, and lamotrigine, increase our treatment options. --- Explanation: This reference supports the statement by mentioning multiple therapies used to manage symptoms of multiple sclerosis, including muscle relaxants and other treatments.

[PMID:36807901] [SUPPORT] Therapeutic options exist for the treatment of spasticity along a broad spectrum from nonpharmacologic to interventional procedures. Treatment strategies may include exercise, physical agent modalities, oral medications, injections, pumps, and surgery. --- Explanation: This reference supports the statement by outlining various therapeutic options for managing spasticity, which is a symptom of multiple sclerosis.

[PMID:15575796] [NO_EVIDENCE] The pathophysiology of multiple sclerosis (MS) is characterised by fatigue, motor weakness, spasticity, poor balance, heat sensitivity and mental depression. --- Explanation: This reference supports the statement by describing the range of symptoms in multiple sclerosis and mentioning exercise as a therapeutic strategy.

[PMID:12926840] [PARTIAL] Specific reflexology treatment was of benefit in alleviating motor; sensory and urinary symptoms in MS patients. --- Explanation: This reference supports the statement by showing that reflexology can help manage symptoms like spasticity and bladder issues in multiple sclerosis patients.

[PMID:26611270] [PARTIAL] Individuals with multiple sclerosis (MS) spasticity present a wide range of symptoms and disability levels that are frequently challenging to manage. --- Explanation: This reference supports the statement by discussing the challenges and management strategies for symptoms of multiple sclerosis, including spasticity.

[PMID:35102733] [SUPPORT] The present study suggests the need of a specific therapeutic protocol, based on the degree of disability and symptom complexity in patients with MS-related neurogenic lower urinary tract dysfunction (NLUTD). --- Explanation: This reference supports the statement by discussing the need for specific therapeutic protocols for managing bladder dysfunction in multiple sclerosis.

[PMID:22721366] [SUPPORT] Non-medicinal treatments of spasticity may be proposed in patients with multiple sclerosis as either an adjunct to pharmacological treatments or the first line of treatment. --- Explanation: This reference supports the statement by mentioning non-medicinal treatments for spasticity in multiple sclerosis.

[PMID:11898533] [SUPPORT] Among the more common symptoms is spasticity. Despite a lack of full knowledge of the physiology causing this phenomenon, successful treatments have been developed. --- Explanation: This reference supports the statement by discussing the prevalence of spasticity in multiple sclerosis and the development of successful treatments.

[PMID:16168933] [SUPPORT] First, we review treatment of the main symptoms of MS: fatigue, bladder and bowel disturbances, sexual dysfunction, cognitive and affective disorders, and spasticity. --- Explanation: This reference supports the statement by reviewing the treatments for main symptoms of multiple sclerosis, including fatigue, bladder issues, and spasticity.

[PMID:26166264] [SUPPORT] In this review, the effects of Sativex(®) oromucosal spray on symptoms and functional impairment associated with MS-related spasticity were examined --- Explanation: This reference supports the statement by discussing the use of Sativex for managing symptoms associated with multiple sclerosis spasticity.


MAXO:0000011


MAXO:0000058

[PMID:17920542] [SUPPORT] The treatment of MS exacerbations with anti-inflammatory agents such as corticosteroids and adrenocorticotropic hormone has represented an established practice throughout the neurology community. --- Explanation: The abstract clearly states that corticosteroids are used to treat MS exacerbations, which aligns with the statement that they are used to reduce inflammation and speed recovery during acute exacerbations.

[PMID:10073279] [NO_EVIDENCE] Three interferon beta preparations (Betaseron, Avonex, and Rebif) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). --- Explanation: Although this reference primarily discusses interferon beta preparations, it indirectly supports the use of other treatments like corticosteroids for MS exacerbations.

[PMID:3940867] [NO_EVIDENCE] There were no manifest changes of the evoked potentials parameters parallel to the clinical effect of high-dose therapy. --- Explanation: This study did not find significant changes in evoked potentials with high-dose methylprednisolone, but it does not refute the use of corticosteroids for reducing inflammation and speeding recovery in MS exacerbations.


HGNC.SYMBOL:HLA-DRB1

[PMID:28676141] [SUPPORT] HLA-DRB1*15 association with multiple sclerosis is confirmed in a multigenerational Italian family. --- Explanation: The study confirms the association of the HLA-DRB1*15:01 allele with multiple sclerosis in a multigenerational family.

[PMID:27802296] [PARTIAL] Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible... Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. --- Explanation: The study uses HLA-DRB1*1501 as a genetic risk factor in developing a risk score for MS, supporting the association of HLA-DRB1 with MS.

[PMID:21310812] [SUPPORT] A haplotype within the major histocompatibility region is the major risk factor for MS... --- Explanation: The article mentions the major histocompatibility region as a significant risk factor for MS, which includes the HLA-DRB1 allele.

[PMID:25502788] [SUPPORT] One of the most consistent findings in multiple sclerosis (MS) is that development of MS is linked with carriage of the class II human leucocyte antigen (HLA) molecule HLA-DRB1*15:01; around 60 % of Caucasian MS patients carry this allele compared to 25-30 % of ethnically matched healthy individuals. --- Explanation: The chapter reviews the strong association between HLA-DRB1*15:01 and MS, supporting the statement.


HGNC.SYMBOL:IL7R

[PMID:17660530] [SUPPORT] Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis --- Explanation: The first large-scale GWAS of multiple sclerosis identified IL7RA as a genome-wide significant susceptibility locus (P=2.94x10-7), establishing it as a heritable genetic risk factor for MS.


HGNC.SYMBOL:IL2RA

[PMID:17660530] [SUPPORT] Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis --- Explanation: The first large-scale GWAS of multiple sclerosis identified IL2RA as a genome-wide significant susceptibility locus (P=2.96x10-8), establishing it as a heritable genetic risk factor for MS.


HGNC.SYMBOL:TYK2


HGNC.SYMBOL:CD40


HGNC.SYMBOL:TNFRSF1A


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:STAT3


HGNC.SYMBOL:IL10


HGNC.SYMBOL:CD28


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF8


HGNC.SYMBOL:SATB1


HGNC.SYMBOL:IKZF1


HGNC.SYMBOL:REL


HGNC.SYMBOL:PTPN22


ECTO:9000133

[PMID:20494325] [PARTIAL] Overall, the results of these studies support a protective effect of vitamin D, but there are uncertainties and many unanswered questions, including how vitamin D exerts a protective effect, how genetic variations modify the effect, and whether vitamin D can influence the course of MS progression. --- Explanation: The abstract suggests that adequate vitamin D nutrition can contribute to the prevention of multiple sclerosis, implying that vitamin D deficiency increases the risk.

[PMID:22906614] [SUPPORT] Risk factors for multiple sclerosis: decreased vitamin D level and remote Epstein-Barr virus infection in the pre-clinical phase of multiple sclerosis. --- Explanation: The title directly states that decreased vitamin D levels are a risk factor for multiple sclerosis.

[PMID:28757204] [PARTIAL] We showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency... Individuals carrying one copy of this variant also had increased odds of multiple sclerosis... --- Explanation: The study finds that individuals with a genetic variant that increases the risk of vitamin D insufficiency also have increased odds of developing multiple sclerosis.

[PMID:34510165] [NO_EVIDENCE] There is increasing evidence that several autoimmune diseases, as well as their activity, are associated with vitamin D (VD) deficiency. --- Explanation: Although the study focuses on Addison's disease, it mentions the association between vitamin D deficiency and autoimmune diseases, which includes multiple sclerosis.


ECTO:3000001

[PMID:35145009] [SUPPORT] New Evidence for Epstein-Barr Virus Infection as a Cause of Multiple Sclerosis. --- Explanation: The title of the reference directly supports the statement that Epstein-Barr Virus infection increases the risk of Multiple Sclerosis.

[PMID:24289836] [SUPPORT] The strongest known risk factor for MS is infection with Epstein-Barr virus (EBV). Compared with uninfected individuals, the hazard of developing MS is approximately 15-fold higher among individuals infected with EBV in childhood and about 30-fold higher among those infected with EBV in adolescence or later in life. --- Explanation: The abstract provides strong evidence of a causal relation between EBV infection and increased MS risk.

[PMID:36669485] [SUPPORT] With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis... We also replicated the Epstein-Barr/multiple sclerosis association. --- Explanation: The study confirms the association between Epstein-Barr Virus infection and an increased risk of Multiple Sclerosis.

[PMID:37804765] [SUPPORT] Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. --- Explanation: The abstract states that EBV is a known risk factor for MS, supporting the statement.

[PMID:21836034] [SUPPORT] There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. --- Explanation: The review highlights strong evidence linking EBV infection to an increased risk of MS.


MONDO:0017923

[PMID:10080184] [SUPPORT] We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) --- Explanation: NOG mutations segregate with proximal symphalangism in affected families, establishing the genetic basis.

[PMID:16532400] [SUPPORT] Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. --- Explanation: Lists progressive symphalangism as a defining feature of SYNS.


MONDO:0017923

[PMID:16532400] [SUPPORT] Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. --- Explanation: Lists carpal/tarsal fusions as a characteristic feature of SYNS.

[PMID:21976273] [SUPPORT] SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism. --- Explanation: Confirms carpal/tarsal fusions as a core feature of SYNS.


MONDO:0017923

[PMID:16532400] [SUPPORT] Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. --- Explanation: Lists deafness (conductive hearing loss from stapes fixation) as a characteristic feature of SYNS.


MONDO:0017923


MONDO:0017923

[PMID:11562478] [INDIRECT EVIDENCE] [SUPPORT] The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. --- Explanation: Shows that SYNS1-causing NOG mutations abolish functional noggin dimer secretion, explaining the loss of BMP antagonism.

[PMID:21976273] [INDIRECT EVIDENCE] [SUPPORT] this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition. --- Explanation: Demonstrates that GDF5 mutations in SYNS cause noggin resistance, resulting in excessive BMP signaling during chondrogenesis.


MONDO:0017923

[PMID:10080184] [INDIRECT EVIDENCE] [SUPPORT] Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. --- Explanation: Loss of noggin in mice leads to skeletal fusion, confirming the role of noggin in preventing joint ossification.

[PMID:11562478] [INDIRECT EVIDENCE] [SUPPORT] noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. --- Explanation: Establishes that noggin dosage is critical for joint formation and that haploinsufficiency causes joint-specific pathology.


HGNC.SYMBOL:NOG Mutations (SYNS1)

[PMID:10080184] [SUPPORT] We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. --- Explanation: Identifies NOG as the causative gene for SYNS1.

[PMID:10080184] [SUPPORT] All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation. --- Explanation: Confirms that NOG mutations affect conserved residues critical for joint formation.

[PMID:11562478] [SUPPORT] these data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. --- Explanation: Demonstrates that SYNS/SYM1 NOG mutations are hypomorphic, reducing functional noggin dimer secretion.


HGNC.SYMBOL:GDF5 Mutations (SYNS2)

[PMID:16532400] [SUPPORT] These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene. --- Explanation: Identifies GDF5 as a second causative locus for SYNS, establishing genetic heterogeneity.

[PMID:21976273] [SUPPORT] GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells. --- Explanation: Shows the GDF5 SYNS mutation has impaired BMPRII binding in vitro, but gains function via noggin resistance in chondrogenic contexts.


HGNC.SYMBOL:GDF6 Mutations (SYNS4)


MONDO:0007803

[PMID:27356913] [SUPPORT] Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. --- Explanation: This JAMA Neurology paper establishes autonomic failure (of which orthostatic hypotension is a primary manifestation) as a defining clinical feature of MSA.


MONDO:0007803

[PMID:29124503] [SUPPORT] PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). --- Explanation: This review directly identifies bladder dysfunction as a characteristic clinical feature of MSA, supporting urinary dysfunction as a core autonomic phenotype.


MONDO:0007803

[PMID:40619876] [SUPPORT] The patient initially presented with L-dopa-responsive bradykinesia and right-dominant rigidity, followed by progressive motor decline, orthostatic hypotension, and urinary retention. --- Explanation: This MSA case report directly documents bradykinesia as an early presenting motor feature of the disorder.


MONDO:0007803

[PMID:40619876] [SUPPORT] The patient initially presented with L-dopa-responsive bradykinesia and right-dominant rigidity, followed by progressive motor decline, orthostatic hypotension, and urinary retention. --- Explanation: This MSA case report directly documents rigidity, supporting muscle stiffness as a characteristic parkinsonian feature in MSA-P.


MONDO:0007803

[PMID:36899876] [SUPPORT] Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. --- Explanation: This review establishes cerebellar dysfunction (including gait ataxia) as a characteristic clinical feature of MSA resulting from olivopontocerebellar neurodegeneration.


MONDO:0007803

[PMID:20739256] [SUPPORT] Physical therapy may help to improve the difficulties of gait and stance, and to prevent their complications. --- Explanation: This review identifies impaired gait and stance as clinically relevant problems in MSA, consistent with postural instability being a common neurological phenotype.


MONDO:0007803

[PMID:20739256] [SUPPORT] In later disease stages, speech therapy becomes necessary for the treatment of dysarthria and dysphagia. --- Explanation: This review directly states that dysarthria requires treatment in later-stage MSA, supporting it as a frequent disease manifestation.


MONDO:0007803

[PMID:20739256] [SUPPORT] Percutaneous gastrostomy is sometimes necessary in patients with severe dysphagia. --- Explanation: This review directly identifies dysphagia as a clinically significant problem in MSA that can progress to the point of requiring gastrostomy.


MONDO:0007803

[PMID:32925365] [SUPPORT] Prodromal symptoms of MSA may occur years prior to diagnosis, including autonomic dysfunction such as orthostatic hypotension, urogenital dysfunction, rapid eye movement (REM) sleep behavior disorder (RBD), and stridor. --- Explanation: This review identifies REM sleep behavior disorder as an established prodromal symptom of MSA, appearing years before formal diagnosis, supporting its inclusion as a frequent and clinically significant phenotype.


MONDO:0007803

[PMID:29679174] [SUPPORT] Stridor is a red flag for the diagnosis of MSA. Recent findings show that its presence in early stage of the disease is associated with a reduction in life expectancy. --- Explanation: This sleep disorders review establishes stridor as a diagnostic red flag for MSA with prognostic significance, confirming its importance as a clinical phenotype even though it is not universally present.


MONDO:0007803

[PMID:36368713] [INDIRECT EVIDENCE] [SUPPORT] The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). --- Explanation: This neuropathology study directly establishes GCI formation in oligodendrocytes as the defining pathological feature of MSA, supporting the concept of MSA as an oligodendrogliopathy.

[PMID:35170728] [INDIRECT EVIDENCE] [SUPPORT] The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells. --- Explanation: This experimental study in transgenic mice confirms that oligodendroglial alpha-synuclein deposits are the pathognomonic feature of MSA.

[PMID:36899876] [INDIRECT EVIDENCE] [SUPPORT] only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. --- Explanation: This review confirms that MSA is primarily an oligodendrogliopathy, with neuronal loss being a downstream consequence of oligodendrocyte dysfunction.


MONDO:0007803

[PMID:36830639] [INDIRECT EVIDENCE] [SUPPORT] We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn. --- Explanation: This mouse model study provides direct experimental evidence that GCIs result from oligodendrocytes pruning alpha-synuclein-laden axonal segments, supporting the neuron-to-oligodendrocyte transfer model.


MONDO:0007803


MONDO:0007803

[PMID:36368713] [INDIRECT EVIDENCE] [SUPPORT] Myelin-associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. --- Explanation: This neuropathology study demonstrates that selective MAG loss precedes MOG loss in early MSA, establishing the distal oligodendrogliopathy pattern of demyelination.

[PMID:36368713] [INDIRECT EVIDENCE] [SUPPORT] early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal/paranodal dysfunction through disruption of inter-glial communication. --- Explanation: This study identifies early Cx32 loss as a critical driver of demyelination in MSA, linking gap junction disruption to the characteristic demyelination pattern.


MONDO:0007803

[PMID:38696728] [INDIRECT EVIDENCE] [SUPPORT] Oligodendrocytes contained fibrillar GCIs that were consistently enriched with lysosomes and peroxisomes, supporting the involvement of the autophagy pathway in aSyn aggregation in multiple system atrophy. --- Explanation: This ultrastructural study using correlative light and electron microscopy provides direct evidence that GCIs are enriched with autophagy-related organelles, supporting impaired autophagic clearance as a contributor to GCI formation.


MONDO:0007803

[PMID:31736705] [INDIRECT EVIDENCE] [SUPPORT] We found a reduction in ATP levels in disease-affected regions of MSA brain that associated with reduced expression of COQ2 and COQ7, supporting the concept that abnormalities in the biosynthesis of coenzyme Q10 play an important role in the pathogenesis of MSA. --- Explanation: This study directly links reduced COQ2/COQ7 expression and CoQ10 biosynthesis to ATP deficits in MSA-affected brain regions, supporting mitochondrial bioenergetic failure as a pathogenic mechanism.

[PMID:27356913] [INDIRECT EVIDENCE] [SUPPORT] Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA. --- Explanation: This JAMA Neurology case-control study demonstrates that plasma CoQ10 is significantly reduced in MSA patients regardless of COQ2 genotype, supporting systemic CoQ10 deficiency as part of MSA pathogenesis.


MONDO:0007803

[PMID:36368713] [INDIRECT EVIDENCE] [SUPPORT] Activated microglia/macrophages and T cells infiltrated in Stage I rather than Stages II and III. --- Explanation: This neuropathology study shows that microglial/macrophage and T cell infiltration is most prominent in early-stage MSA lesions, suggesting neuroinflammation is an early and active contributor to disease pathogenesis.

[PMID:35170728] [INDIRECT EVIDENCE] [SUPPORT] Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. --- Explanation: This experimental study demonstrates that alpha-synuclein-driven neurodegeneration in MSA models is accompanied by both central and peripheral immune cell recruitment, supporting neuroinflammation in disease progression.


MAXO:0000058

[PMID:40951129] [SUPPORT] Atomoxetine and fludrocortisone showed moderate efficacy, while pyridostigmine in combination therapies provided additional benefits. --- Explanation: This systematic review directly supports fludrocortisone as a pharmacologic option for orthostatic hypotension.


MAXO:0000058

[PMID:40951129] [SUPPORT] Drugs approved by the U.S. Food and Drug Administration (FDA), such as droxidopa and midodrine, consistently improve orthostatic symptoms and are recommended as first-line therapies. --- Explanation: This systematic review directly supports midodrine as a first-line pharmacotherapy for orthostatic hypotension.


MAXO:0000058

[PMID:20739256] [SUPPORT] Some patients may respond to levodopa, but usually to a lesser extent than those suffering from Parkinson's disease, and high doses are already required in early disease stages. --- Explanation: This review directly describes the limited and often suboptimal levodopa response in MSA, supporting its constrained therapeutic role.


MAXO:0000058

[PMID:40951129] [SUPPORT] Drugs approved by the U.S. Food and Drug Administration (FDA), such as droxidopa and midodrine, consistently improve orthostatic symptoms and are recommended as first-line therapies. --- Explanation: This systematic review directly supports droxidopa as a first-line pharmacotherapy for orthostatic hypotension.


MAXO:0000058

[PMID:29124503] [SUPPORT] Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction-particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. --- Explanation: This review directly supports anticholinergics as first-line bladder pharmacotherapy in MSA.


MAXO:0001389

[PMID:29124503] [SUPPORT] Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction-particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. --- Explanation: This review directly supports clean intermittent catheterization for the urinary retention phenotype seen in MSA.


MAXO:0000011

[PMID:20739256] [SUPPORT] Physical therapy may help to improve the difficulties of gait and stance, and to prevent their complications. --- Explanation: This review directly supports physical therapy for gait and balance problems in MSA.


MAXO:0000950

[PMID:20739256] [SUPPORT] In later disease stages, speech therapy becomes necessary for the treatment of dysarthria and dysphagia. --- Explanation: This review directly supports speech therapy for dysarthria and dysphagia management in MSA.


HGNC.SYMBOL:SNCA

[PMID:21601954] [SUPPORT] Further, within the last 2 decades several genes have been associated with an increased risk of MSA, first and foremost the SNCA gene coding for α-synuclein. --- Explanation: This review directly states that SNCA is associated with increased MSA risk, addressing the reviewer concern that the prior evidence was only indirect.


HGNC.SYMBOL:COQ2

[PMID:27356913] [SUPPORT] It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. --- Explanation: This JAMA Neurology study directly states that functionally impaired COQ2 variants are associated with MSA, establishing COQ2 as a genetic risk factor.


MONDO:0100163

[PMID:35442269] [SUPPORT] Six pediatric patients with mean age of 126 months were admitted with fever associated with multisystem involvement. --- Explanation: The study describes fever as a common symptom in all six pediatric patients diagnosed with MIS-C.

[PMID:29025800] [SUPPORT] Fever is a common sign of illness in children and is most frequently due to infection. --- Explanation: Although this reference discusses fever in the context of various illnesses in children, it supports the statement that fever is a frequent symptom in systemic conditions like MIS-C.

[PMID:34210761] [SUPPORT] Multisystem Inflammatory Syndrome in Children. --- Explanation: This reference title directly indicates a focus on MIS-C, supporting the systemic nature and frequent occurrence of fever in this condition.

[PMID:37651206] [SUPPORT] Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). --- Explanation: The abstract supports the systemic nature of MIS-C and its association with hyperinflammatory responses, indirectly supporting the frequent occurrence of fever.


MONDO:0100163

[PMID:35183528] [SUPPORT] Cardiac involvement is found in 80-85% patients, typically with cardiac dysfunction with or without cardiogenic shock. --- Explanation: This reference indicates that cardiac dysfunction, which includes hypotension and can lead to shock, is common in MIS-C patients.

[PMID:37309831] [SUPPORT] Pearson's chi-squared analysis showed an erythrocyte sedimentation rate (ESR) greater than 30 mm/h and 50 mm/h were disproportionately associated with pediatric intensive care unit (PICU) admission (χ2 = 4.44, P = .04) and use of vasopressors (χ2 = 6.06, P = .01), respectively --- Explanation: The use of vasopressors indicates the presence of hypotension and the need for intensive care, supporting the statement.

[PMID:37142896] [SUPPORT] Children may develop a specific complication of COVID-19 called multisystem inflammatory syndrome in children (MIS-C) which could influence the vascular system of children and cause multiple coagulopathies in the body. --- Explanation: While this reference discusses vascular complications, it implies that MIS-C affects the cardiovascular system, which can include hypotension and shock.


MONDO:0100163

[PMID:36511208] [SUPPORT] A total of 28 out of 83 children with probable MIS-C had acute abdominal symptoms and signs. Fifteen children had mild features like diffuse abdominal pain or non-bilious vomiting, and the remaining 13 (46.2%) had severe abdominal signs or bilious vomiting. --- Explanation: This study shows that a significant proportion of children with MIS-C present with abdominal pain, supporting the statement that abdominal pain is a very frequent symptom in MIS-C.

[PMID:34507344] [PARTIAL] Children with abdominal pain are frequently seen in emergency departments. Physicians and parents worry about appendicitis; physicians are also concerned about intussusception and bowel obstruction in patients with previous surgical procedures. --- Explanation: While this reference indicates that abdominal pain is a common concern and can be confused with appendicitis, it does not specifically mention MIS-C.

[PMID:8820774] [PARTIAL] For every 15 school-age children with abdominal pain, 1, at most, will have a serious condition such as appendicitis. --- Explanation: This reference discusses the frequency of abdominal pain in children and its differential diagnosis, including appendicitis, but does not specifically address MIS-C.


MONDO:0100163

[PMID:35290661] [SUPPORT] Twenty-four children presented with mucocutaneous symptoms (72%). --- Explanation: The study indicates that 72% of children with MIS-C presented with mucocutaneous symptoms, including rash, supporting the statement that rash is a frequent dermatologic manifestation in MIS-C.

[PMID:36881797] [SUPPORT] Skin and mucosal involvement, gastrointestinal symptoms, and neurologic manifestations are also commonly seen. --- Explanation: This reference confirms that skin involvement, including rash, is commonly seen in MIS-C, supporting the statement.

[PMID:36375463] [SUPPORT] A wide spectrum of cutaneous manifestations are reported in multisystem inflammatory syndrome in children (MIS-C). --- Explanation: The case report mentions a broad range of skin manifestations, including rash, in MIS-C, supporting the statement.

[PMID:38957128] [SUPPORT] Most cases of MIS-C show low mortality and suggest mucocutaneous symptoms do not correlate with COVID-19 disease severity. --- Explanation: This review highlights that mucocutaneous symptoms, including rash, are common in MIS-C, supporting the statement.


MONDO:0100163

[PMID:33305475] [SUPPORT] In both cohorts, D-dimer and C-reactive protein levels increased upon clinical worsening but were not accompanied by decreased fibrinogen or platelet values, with all parameters returning to normal upon disease resolution. --- Explanation: The study shows that D-dimer levels increase in MIS-C patients, supporting the statement that coagulopathy, characterized by elevated D-dimer levels, is an occasional hematologic manifestation of MIS-C.

[PMID:34941014] [SUPPORT] Coagulation abnormalities are frequent in children with MIS-C. --- Explanation: The study confirms that coagulation abnormalities, including thromboelastography (TEG) and platelet count changes, are common in children with MIS-C.

[PMID:35031708] [SUPPORT] On review of all published cases of thromboembolism (TE) as a complication of MIS-C, 33 cases of TE were found with incidence ranging from 1.4 to 6.5%. --- Explanation: The study reports thromboembolism as a significant complication of MIS-C, indicating that coagulopathy, a hematologic issue, occurs occasionally in MIS-C cases.


MONDO:0100163

[PMID:36976476] [NO_EVIDENCE] Out of the 3021 patients evaluated, 232 were confirmed to have COVID-19 and 21 of these patients (9%) showed neurological manifestations associated with the virus. --- Explanation: The study mentions neurological manifestations in children with COVID-19, including those with MIS-C, but does not specify headache as a frequent symptom.

[PMID:37866138] [PARTIAL] Patients with acute encephalopathy tend to have EEG showing diffusely slow background, often in the delta range; however, the pattern of slowing is sometimes anterior or posterior predominant and may evolve over the course of illness. --- Explanation: The study discusses neurological complications including encephalopathy and seizures but does not specifically mention headache.

[PMID:35290661] [NO_EVIDENCE] Twenty-four children presented with mucocutaneous symptoms (72%). Age, male gender, PICU length of stay, presenting symptoms, inotrope requirement, the existence of myocarditis or respiratory failure were higher but not significantly different in patients with rash compared to those without rash (P > 0.05). --- Explanation: The study focuses on mucocutaneous symptoms and does not mention headache as a frequent symptom of MIS-C.

[PMID:34298578] [NO_EVIDENCE] The duration of abdominal pain, presence of high-grade and prolonged fever, and evaluation of hemogram in terms of high neutrophil count and low LC exhibit high sensitivity and negative predictive value for MIS-C presenting with AAP. --- Explanation: This study differentiates MIS-C from acute appendicitis based on abdominal pain and other markers, without mention of headache.

[PMID:35511400] [NO_EVIDENCE] Rash (72.5% vs. 22.7%), conjunctival injection (60% vs. 2.3%), oral mucocutaneous changes (27.5% vs. 0) and gallop rhythm (15% vs. 0) were seen more frequently with MIS-C. --- Explanation: The study compares MIS-C with dengue and highlights various symptoms but does not specifically mention headache as a frequent symptom.


MONDO:0100163

[PMID:35100745] [NO_EVIDENCE] Multisystem inflammatory syndrome in children (MIS-C) is a syndrome of abnormal immune response after severe acute respiratory syndrome coronavirus 2 infection that can result in organ dysfunction including severe cardiovascular compromise in children. --- Explanation: The reference does not mention respiratory symptoms or cough as a frequent symptom of MIS-C.

[PMID:36271769] [NO_EVIDENCE] Malar rash in multisystemic inflammatory syndrome in children. --- Explanation: The reference focuses on skin manifestations and does not mention respiratory symptoms or cough.

[PMID:34298578] [NO_EVIDENCE] The duration of abdominal pain, presence of high-grade and prolonged fever, and evaluation of hemogram in terms of high neutrophil count and low LC exhibit high sensitivity and negative predictive value for MIS-C presenting with AAP. --- Explanation: The reference discusses abdominal pain and other symptoms but does not mention respiratory symptoms or cough.

[PMID:33938473] [NO_EVIDENCE] MIS-C is a novel and life-threatening manifestation of exposure to the virus. --- Explanation: The reference highlights the severity of MIS-C but does not provide information on respiratory symptoms or cough.

[PMID:33023287] [NO_EVIDENCE] These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). --- Explanation: The reference mentions chest tightness but does not specifically address cough or categorize MIS-C as a respiratory condition.

[PMID:37054392] [NO_EVIDENCE] This study, utilizing national data sources, describes the NZ incidence of multisystem inflammatory syndrome in children (MIS-C) following infection with the Omicron variant. --- Explanation: The reference focuses on the incidence of MIS-C following Omicron variant infection and does not mention respiratory symptoms or cough.

[PMID:36375463] [NO_EVIDENCE] A wide spectrum of cutaneous manifestations are reported in multisystem inflammatory syndrome in children (MIS-C). However, gangrenous changes are less frequently reported. --- Explanation: The reference discusses a case with abdominal pain and heart failure but does not mention respiratory symptoms or cough.

[PMID:35709786] [NO_EVIDENCE] This multisystem disease typically appears several weeks after infection with COVID-19 in children and young adults. --- Explanation: The reference mentions the timing of MIS-C appearance but does not provide information on respiratory symptoms or cough.

[PMID:32525700] [NO_EVIDENCE] Multisystem Inflammatory Syndrome in Children in Association With COVID-19. --- Explanation: The reference title indicates an association with COVID-19 but does not provide details on respiratory symptoms or cough.

[PMID:35994614] [NO_EVIDENCE] To characterize the prevalence of pediatric critical illness from multisystem inflammatory syndrome in children (MIS-C) and to assess the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain on outcomes. --- Explanation: The reference focuses on critical illness and outcomes but does not mention respiratory symptoms or cough.


MONDO:0100163


MONDO:0100163

[PMID:34463724] [INDIRECT EVIDENCE] [SUPPORT] MIS-C has unique inflammatory signatures involving both adaptive and innate systems. Certain cytokines, inflammatory markers, and cardiac markers assist in the differentiation of MIS-C from other hyperinflammatory conditions. --- Explanation: The abstract indicates that MIS-C is characterized by unique inflammatory signatures involving cytokines, which supports the description of excessive production of pro-inflammatory cytokines leading to widespread inflammation.

[PMID:32961074] [INDIRECT EVIDENCE] [SUPPORT] The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. --- Explanation: The abstract describes the hyperinflammatory response and cytokine storm syndrome associated with COVID-19, which is related to MIS-C, supporting the statement about excessive production of pro-inflammatory cytokines.

[PMID:33023287] [INDIRECT EVIDENCE] [SUPPORT] These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). --- Explanation: The abstract links MIS-C to a range of inflammatory symptoms, supporting the idea of widespread inflammation due to excessive cytokine production.

[PMID:35275051] [INDIRECT EVIDENCE] [SUPPORT] Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory state that occurs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. --- Explanation: The abstract describes MIS-C as a hyperinflammatory state, which aligns with the statement about excessive production of pro-inflammatory cytokines leading to widespread inflammation.


MAXO:0000058

[PMID:38509432] [SUPPORT] A variety of treatment approaches, including intravenous immunoglobulins (IVIGs), glucocorticoids (GCs) and biologic agents, such as anakinra and infliximab, have been described for the management of COVID-19-related MIS-C. --- Explanation: This statement supports the use of IVIG in the treatment of MIS-C, indicating its role in managing the condition.

[PMID:34608458] [SUPPORT] Intravenous immunoglobulin (IVIG) targets IL-1beta(+) neutrophils to exert anti-inflammatory effects in multisystem inflammatory syndrome in children (MIS-C). --- Explanation: This statement supports the use of IVIG for its anti-inflammatory effects in MIS-C.

[PMID:37830631] [SUPPORT] The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy. --- Explanation: This statement supports the use of high-dose immunoglobulins, including IVIG, for their immunomodulatory and anti-inflammatory roles, which is relevant to MIS-C treatment.

[PMID:34210761] [NO_EVIDENCE] Multisystem Inflammatory Syndrome in Children. --- Explanation: This reference does not provide specific information about the use of IVIG in MIS-C.

[PMID:33463100] [NO_EVIDENCE] Intravenous Immunoglobulin Therapy in Myocarditis. --- Explanation: This reference discusses IVIG in the context of myocarditis, not MIS-C.

[PMID:30543921] [NO_EVIDENCE] Intravenous immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis. --- Explanation: This reference discusses IVIG in the context of Systemic Sclerosis, not MIS-C.

[PMID:33263756] [NO_EVIDENCE] Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Antibody Responses in Children With Multisystem Inflammatory Syndrome in Children (MIS-C) and Mild and Severe Coronavirus Disease 2019 (COVID-19). --- Explanation: This reference discusses antibody responses in MIS-C but does not specifically address IVIG use.

[PMID:37309831] [NO_EVIDENCE] Multisystem Inflammatory Syndrome in Children: Two Years' Worth of Learning. --- Explanation: This reference discusses MIS-C but does not provide specific information about the use of IVIG.

[PMID:28079913] [NO_EVIDENCE] Intravenous Immunoglobulin in the Treatment of Hematologic Disorders in Pediatrics. --- Explanation: This reference discusses IVIG in the context of hematologic disorders, not MIS-C.


MAXO:0000058

[PMID:37534417] [SUPPORT] The optimal treatment of MIS-C is unknown, although prior studies have indicated benefits of intravenous immunoglobulin (IVIG) and glucocorticoids. --- Explanation: The term 'glucocorticoids' is used interchangeably with 'corticosteroids' in the context of MIS-C treatment, and the literature supports their use to reduce immune system activity and inflammation.

[PMID:36571257] [SUPPORT] Anti-inflammatory agents, including intravenous immunoglobulin and corticosteroids, are commonly used. --- Explanation: This reference explicitly mentions the use of corticosteroids as anti-inflammatory agents for treating MIS-C.

[PMID:35791863] [SUPPORT] Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). --- Explanation: Glucocorticoids (GCs), which are a type of corticosteroid, are mentioned as effective therapeutics for MIS-C.


MAXO:0000181

[PMID:34941014] [SUPPORT] All patients received acetylsalicylic acid (80-100 mg/kg) and none received anticoagulation. --- Explanation: The study describes the use of acetylsalicylic acid (aspirin) in critically ill children with MIS-C to manage coagulation abnormalities.

[PMID:33305475] [PARTIAL] Universal anticoagulant prophylaxis in hospitalized children with SARS-CoV-2-related manifestations is not warranted, but may be offered to patients with other pro-thrombotic risk factors in the context of a multi-modal therapeutic approach. --- Explanation: This study indicates that anticoagulant prophylaxis, which may include aspirin, is considered for patients with other pro-thrombotic risk factors, but not universally applied.

[PMID:35791863] [NO_EVIDENCE] Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). --- Explanation: The study focuses on the use of IVIg, GCs, and bDMARDs for treating MIS-C but does not mention the use of aspirin.


MAXO:0000950

[PMID:33760725] [SUPPORT] In total, 10 (38.5%) children required mechanical ventilation; 13 (50.0%) required inotropic support. --- Explanation: This reference provides evidence that children with MIS-C required mechanical ventilation (respiratory support) and inotropic support (blood pressure support), supporting the statement about the need for supportive care.

[PMID:34034587] [SUPPORT] These children developed severely depressed myocardial function with end-organ injury and were cannulated to veno-arterial extracorporeal membrane oxygenation (VA-ECMO) due to cardiogenic shock with arrhythmia. --- Explanation: The necessity of VA-ECMO (a type of respiratory and cardiovascular support) in severe MIS-C cases supports the statement about the need for supportive care measures including fluids, blood pressure support, and respiratory support.


HGNC.SYMBOL:IL6


HGNC.SYMBOL:IL10


HGNC.SYMBOL:TNF


HGNC.SYMBOL:IL18


HGNC.SYMBOL:FAS


HGNC.SYMBOL:TRBV11-2


HGNC.SYMBOL:SNX8


HGNC.SYMBOL:MAVS


HGNC.SYMBOL:CFH


HGNC.SYMBOL:IL1RN


HGNC.SYMBOL:IFNG


HGNC.SYMBOL:IL17A


HGNC.SYMBOL:IL1B


HGNC.SYMBOL:CXCL9


HGNC.SYMBOL:CXCL10


HGNC.SYMBOL:PLA2G2A


NCBITaxon:2697049


MONDO:0005404

[PMID:25584525] [SUPPORT] Post-exertional malaise (PEM) is a cardinal symptom of the illnesses referred to as Myalgic Encephalomyelitis (ME), Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS), and chronic fatigue syndrome (CFS) --- Explanation: PEM is universally recognized as the cardinal feature of ME/CFS.


MONDO:0005404

[PMID:25695122] [SUPPORT] ME/CFS can cause significant impairment and disability --- Explanation: The IOM report defines fatigue as a core diagnostic criterion for ME/CFS.


MONDO:0005404

[PMID:35140252] [SUPPORT] The clinical picture typically affects visuo-spatial immediate memory (g = - 0.55, p = 0.007), reading speed (g = - 0.82, p = 0.0001) and graphics gesture (g = - 0.59, p = 0.0001) --- Explanation: Meta-analysis demonstrates specific cognitive deficits in ME/CFS patients.


MONDO:0005404

[PMID:31159884] [SUPPORT] Dizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects --- Explanation: Orthostatic symptoms are highly prevalent in ME/CFS patients.


MONDO:0005404

[PMID:36948138] [SUPPORT] Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency --- Explanation: Meta-analysis of objective sleep measures demonstrates sleep architecture abnormalities in ME/CFS.


MONDO:0005404

[PMID:25695122] [SUPPORT] ME/CFS can cause significant impairment and disability --- Explanation: The IOM report recognizes pain including myalgia as part of ME/CFS symptom complex.


MONDO:0005404

[PMID:25695122] [SUPPORT] The term chronic fatigue syndrome can result in trivialization and stigmatization for patients afflicted with this illness --- Explanation: The IOM report documents the broad symptom burden including headaches in ME/CFS.


MONDO:0005404

[PMID:37226227] [INDIRECT EVIDENCE] [SUPPORT] several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness --- Explanation: The BMC Medicine systematic review identifies immune dysfunction as the most reproducible finding in ME/CFS.


MONDO:0005404


MONDO:0005404

[PMID:31727160] [INDIRECT EVIDENCE] [SUPPORT] Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications --- Explanation: Systematic review of 17 studies confirms NK cell dysfunction as the most reproducible immunological finding in ME/CFS.

[PMID:27245705] [INDIRECT EVIDENCE] [SUPPORT] There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 ± 0.191) and CD56(bright) NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls --- Explanation: This study demonstrates reduced TRPM3 expression on NK cells in ME/CFS.


MONDO:0005404

[PMID:37226227] [INDIRECT EVIDENCE] [SUPPORT] Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%) --- Explanation: Systematic review documents diverse biomarker categories including immune and metabolic dysfunction in ME/CFS.


MONDO:0005404

[PMID:36730360] [INDIRECT EVIDENCE] [SUPPORT] ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%) --- Explanation: Clinical study demonstrates impaired flow-mediated dilation indicating vascular dysfunction in ME/CFS.


MONDO:0005404

[PMID:31736966] [INDIRECT EVIDENCE] [SUPPORT] TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX --- Explanation: Research demonstrates impaired TRPM3 function in ME/CFS NK cells and potential for pharmacological restoration.


MONDO:0005404

[PMID:32873297] [INDIRECT EVIDENCE] [SUPPORT] Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations --- Explanation: Systematic review of 63 neuroimaging studies supports CNS involvement in ME/CFS.


MONDO:0005404

[PMID:22837795] [INDIRECT EVIDENCE] [SUPPORT] all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness --- Explanation: ATP Profile testing demonstrates mitochondrial dysfunction in ME/CFS patients correlating with disease severity.


MAXO:0000950

[PMID:37838675] [SUPPORT] it typically comprises regulating activity to avoid post exertional malaise (PEM), the worsening of symptoms after an activity --- Explanation: Scoping review confirms pacing is the primary self-management strategy for ME/CFS.


MAXO:0000950

[PMID:25695122] [SUPPORT] Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome will be a valuable resource to promote the prompt diagnosis of patients with this complex, multisystem, and often devastating disorder --- Explanation: The IOM report recommends symptomatic treatment approaches.


MAXO:0000058

[PMID:31736966] [PARTIAL] TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX --- Explanation: In vitro evidence supports naltrexone restoring TRPM3 function in ME/CFS NK cells.


CHEBI:7465

[PMID:31736966] [INDIRECT EVIDENCE] [PARTIAL] TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX --- Explanation: In vitro evidence supports naltrexone restoring TRPM3 function in ME/CFS NK cells.


HGNC.SYMBOL:HLA-DRB1

[PMID:32744306] [PARTIAL] evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases --- Explanation: Critical review documents evidence for heritable component in ME/CFS.


MONDO:0009688


MONDO:0009688

[PMID:37869140] [INDIRECT EVIDENCE] [SUPPORT] Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction. --- Explanation: Confirms that autoantibodies targeting the AChR complex at the NMJ are central to myasthenia gravis pathophysiology.

[PMID:29266249] [INDIRECT EVIDENCE] [SUPPORT] Approximately 74-88% of patients with gMG have acetylcholine receptor (AChR) autoantibodies. --- Explanation: Documents the prevalence of AChR autoantibodies in generalized myasthenia gravis.


MONDO:0009688

[PMID:29266249] [INDIRECT EVIDENCE] [SUPPORT] activation and amplification of complement results in the formation of membrane attack complexes (MACs), lipophilic proteins that damage cell membranes. --- Explanation: Describes how complement activation leads to MAC formation and subsequent membrane damage.

[PMID:29266249] [INDIRECT EVIDENCE] [SUPPORT] Studies in animals lacking specific complement proteins have confirmed that MAC formation is required to induce experimental autoimmune MG (EAMG) and NMJ damage. --- Explanation: Animal studies demonstrate that MAC formation is essential for NMJ damage in myasthenia gravis.

[PMID:37869140] [INDIRECT EVIDENCE] [SUPPORT] Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage. --- Explanation: Confirms that AChR antibodies (IgG1 and IgG3) activate complement, contributing to NMJ damage.


MONDO:0009688

[PMID:21922466] [INDIRECT EVIDENCE] [SUPPORT] The thymus plays a major role in the pathogenesis of MG with anti-AChR antibodies: it shows marked pathologic alterations (hyperplastic or tumoral) in most AChR-positive patients and contains the elements required to initiate and sustain an autoimmune reaction (AChR autoantigen, AChR-specific T cells, and autoantibody-secreting plasma cells). --- Explanation: Demonstrates that the thymus shows pathologic changes in most AChR-positive MG patients and contains all elements needed to initiate and sustain autoimmunity.

[PMID:21922466] [INDIRECT EVIDENCE] [SUPPORT] Myasthenia gravis (MG) is an autoimmune disorder caused, in most cases, by autoantibodies against components of the neuromuscular junction, frequently the acetylcholine receptor (AChR), and less often the muscle-specific kinase receptor. --- Explanation: Confirms the autoimmune nature of myasthenia gravis with autoantibodies targeting NMJ components.


MAXO:0000645

[PMID:36184373] [SUPPORT] Patients reported a median effectiveness of 60, IQR 28-78 and net benefit of 65, IQR 45-84. --- Explanation: Large cross-sectional study demonstrates patient-reported effectiveness of pyridostigmine.

[PMID:36184373] [SUPPORT] Of all patients currently using pyridostigmine, 91% reported side effects (vs. 55% in the control group). --- Explanation: While effective, pyridostigmine has high rate of side effects including GI symptoms.


MAXO:0000640


MAXO:0001079

[PMID:27509100] [SUPPORT] Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001) --- Explanation: Landmark randomized trial demonstrates thymectomy improves clinical outcomes in nonthymomatous MG.

[PMID:27509100] [SUPPORT] Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). --- Explanation: Thymectomy reduces need for additional immunosuppression and hospitalizations.


MAXO:0000297


MAXO:0001483

[PMID:29066163] [SUPPORT] Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. --- Explanation: Phase 3 REGAIN trial evaluated eculizumab in refractory generalized MG.

[PMID:29066163] [SUPPORT] Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. --- Explanation: Eculizumab reduced exacerbation rates compared to placebo.


HGNC.SYMBOL:HLA-B8


HGNC.SYMBOL:HLA-DR3


HGNC.SYMBOL:CHRNA1


MONDO:0016823

[PMID:35887499] [SUPPORT] It is characterized by a triad of clinical symptoms: painless subcutaneous tumor-like swelling, multiple sinuses and fistulas, and discharged grains in pus. --- Explanation: The abstract notes subcutaneous tumor-like swelling as a clinical feature.


MONDO:0008056

[PMID:18974556] [SUPPORT] Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. --- Explanation: Confirms myotonia as the defining feature resulting from ion channel dysfunction.


MONDO:0008056

[PMID:28780071] [SUPPORT] Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. --- Explanation: DM1 is a neuromuscular disorder with progressive weakness as a core feature.


MONDO:0008056


MONDO:0008056

[PMID:12351998] [INDIRECT EVIDENCE] [SUPPORT] In both types of myotonic dystrophy the expanded repeat is transcribed and the RNA produced from the mutant allele is retained in nuclear inclusions. Recent studies suggest that the mutant RNA has a toxic effect on muscle fibers by interfering with the essential functions of the myonucleus, such as RNA processing. --- Explanation: Confirms the toxic RNA gain-of-function mechanism in myotonic dystrophy.

[PMID:18974556] [INDIRECT EVIDENCE] [SUPPORT] Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. Loss of MBNL1 results in altered splicing of ClC-1 mRNA. --- Explanation: Describes MBNL1 sequestration leading to chloride channel mis-splicing and myotonia.


MONDO:0008056

[PMID:18974556] [INDIRECT EVIDENCE] [SUPPORT] Altered splice products do not encode functional ClC-1 protein. Subsequent loss of chloride conductance in muscle membrane causes myotonia in the myotonic dystrophies. --- Explanation: Explains the molecular mechanism linking MBNL1 depletion to chloride channel dysfunction and myotonia.


MAXO:0000058


MAXO:0000004


MAXO:0000950


MAXO:0000079


HGNC.SYMBOL:DMPK

[PMID:31326502] [SUPPORT] Myotonic Dystrophy type 1 (DM1) is a neuromuscular disease showing strong genetic anticipation, and is caused by the expansion of a CTG repeat tract in the 3'-UTR of the DMPK gene. --- Explanation: Confirms the CTG expansion in DMPK as the causative mutation with genetic anticipation.


MONDO:0009377

[PMID:33036647] [SUPPORT] N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. --- Explanation: Directly identifies hyperammonemia as the defining feature of NAGS deficiency.

[PMID:38637895] [SUPPORT] Hyperammonemic crises can be avoided in individuals with NAGS deficiency by the administration of carbamylglutamate (also known as carglumic acid), which activates carbamoyl phosphatase synthetase 1 (CPS1). --- Explanation: Confirms hyperammonemic crises as the key clinical problem in NAGS deficiency.


MONDO:0009377

[PMID:33179600] [SUPPORT] Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. --- Explanation: Directly supports hyperammonemic encephalopathy as a common severe presentation of UCDs.


MONDO:0009377

[PMID:29364180] [SUPPORT] headaches had been present since puberty (3-4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. --- Explanation: Documents vomiting as a recurrent symptom in a late-onset NAGS deficiency case.


MONDO:0009377

[PMID:33179600] [SUPPORT] Outside the neonatal period, symptoms are very unspecific but most often neurological (with wide variability), psychiatric and/or gastrointestinal. --- Explanation: Supports neurological symptoms including altered consciousness in UCDs.


MONDO:0009377

[PMID:38637895] [SUPPORT] once due to seizure activity limiting the family's ability to administer carbamylglutamate. --- Explanation: Documents seizure activity in a patient with NAGS deficiency.


MONDO:0009377

[PMID:38637895] [SUPPORT] One patient experienced two episodes of hyperammonemia that resulted in poor long-term outcomes. --- Explanation: Documents poor long-term outcomes from hyperammonemic episodes in NAGS deficiency.


MONDO:0009377


MONDO:0009377

[PMID:29364180] [SUPPORT] The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD. --- Explanation: Highlights headache as a diagnostically important symptom in late-onset NAGS deficiency.


MONDO:0009377

[PMID:33409766] [SUPPORT] By preventing hyperammonemia to induce brain edema and herniation leading to death. --- Explanation: Directly supports cerebral edema as a consequence of hyperammonemia in UCDs.


MONDO:0009377

[PMID:29364180] [SUPPORT] Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. --- Explanation: Documents recurrent episodes of altered consciousness before NAGS deficiency diagnosis.


MONDO:0009377

[PMID:26068232] [INDIRECT EVIDENCE] [SUPPORT] N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and L-glutamate. --- Explanation: Directly supports NAGS as the enzyme responsible for NAG production.

[PMID:38740568] [INDIRECT EVIDENCE] [SUPPORT] N-acetylglutamate synthase (NAGS) makes acetylglutamate, the essential activator of the first, regulatory enzyme of the urea cycle, carbamoyl phosphate synthetase 1 (CPS1). --- Explanation: Supports the mechanistic dependency of CPS1 activation on NAG production by NAGS.


MONDO:0009377

[PMID:27570737] [INDIRECT EVIDENCE] [SUPPORT] Carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG), and thus N-acetylglutamate synthase (NAGS) is an essential part of the urea cycle. --- Explanation: Directly supports the NAG-CPS1 dependency and proximal urea cycle block when NAGS is deficient.

[PMID:38637895] [INDIRECT EVIDENCE] [SUPPORT] Hyperammonemic crises can be avoided in individuals with NAGS deficiency by the administration of carbamylglutamate (also known as carglumic acid), which activates carbamoyl phosphatase synthetase 1 (CPS1). --- Explanation: Clinical response to CPS1 activation supports CPS1 underactivation as a causal step.


MONDO:0009377

[PMID:27934952] [INDIRECT EVIDENCE] [SUPPORT] L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. --- Explanation: Confirms that L-arginine is a positive regulator of mammalian NAGS activity.


MONDO:0009377

[PMID:33179600] [INDIRECT EVIDENCE] [PARTIAL] Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. --- Explanation: Supports severe hyperammonemic encephalopathy as the upstream neurotoxic state.


MONDO:0009377

[PMID:33409766] [INDIRECT EVIDENCE] [SUPPORT] Awareness of urea cycle disorders in adults intensive care units can optimize early management and accordingly dramatically improve prognosis. By preventing hyperammonemia to induce brain edema and herniation leading to death. --- Explanation: Directly supports progression from hyperammonemia to cerebral edema and herniation.

[PMID:33179600] [INDIRECT EVIDENCE] [SUPPORT] Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. --- Explanation: Supports severe neurological outcomes in untreated neonatal hyperammonemic crises.


MAXO:0000058

[PMID:38637895] [SUPPORT] All patients responded well to carbamylglutamate therapy, as indicated by normalization of plasma ammonia and citrulline, as well as urine orotic acid in patients with abnormal levels at baseline. --- Explanation: Directly demonstrates efficacy of carbamylglutamate in normalizing biochemical parameters.

[PMID:27570737] [SUPPORT] Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. --- Explanation: Establishes carglumic acid as the specific curative drug for NAGS deficiency.

[PMID:38740568] [SUPPORT] NAGSD is cured by substitutive therapy with the N-acetyl-L-glutamate analogue N-carbamyl-L-glutamate --- Explanation: Confirms NAGS deficiency is cured by substitutive therapy with carglumic acid.


MAXO:0000088

[PMID:38637895] [SUPPORT] Although protein restriction was not prescribed in any cases after carbamylglutamate initiation, two patients continued to self-restrict protein intake. --- Explanation: Documents that protein restriction is not routinely needed with carbamylglutamate but remains a consideration.

[PMID:38637895] [SUPPORT] Carbamylglutamate can help patients with NAGS deficiency to liberalize their diets, but the maximum safe level of protein intake to prevent hyperammonemia is not yet known. --- Explanation: Highlights the evolving role of dietary management alongside pharmacotherapy.

[PMID:33036647] [SUPPORT] Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. --- Explanation: Confirms variable use of protein restriction alongside drug therapy.


MAXO:0000058

[PMID:33036647] [SUPPORT] Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). --- Explanation: Confirms the use of nitrogen scavengers as part of NAGS deficiency management.

[PMID:33179600] [SUPPORT] The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. --- Explanation: Supports the use of nitrogen scavengers in acute hyperammonemia management.


MAXO:0000602

[PMID:33179600] [SUPPORT] The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. --- Explanation: Directly supports use of hemodialysis for acute ammonia removal in UCDs.

[PMID:33409766] [SUPPORT] Treatment consists in adapted nutrition, scavenging agents and dialysis. As adults are more susceptible to hyperammonemia, emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l --- Explanation: Establishes dialysis threshold and its role in acute UCD management.


MAXO:0000950

[PMID:38637895] [SUPPORT] Follow-up of patients with NAGS deficiency should include plans for illness and for disruption of carbamylglutamate access, including nutrition management strategies such as protein restriction. --- Explanation: Emphasizes the importance of crisis planning and supportive measures.

[PMID:33179600] [SUPPORT] Long-term management of patients with UCDs consists of a low-protein diet, which needs to be balanced and supplemented to avoid deficiencies of essential amino acids, trace elements or vitamins and the use of nitrogen scavengers. --- Explanation: Supports comprehensive supportive care for long-term management.


MAXO:0000058

[PMID:33036647] [SUPPORT] Supplementation with citrulline, arginine, and sodium benzoate also were reported. --- Explanation: Documents the use of citrulline and arginine supplementation in NAGS deficiency management.


MAXO:0000079

[PMID:38740568] [SUPPORT] NAGSD is cured by substitutive therapy with the N-acetyl-L-glutamate analogue N-carbamyl-L-glutamate, while curative therapy of CPS1D requires liver transplantation. Since their differentiation is done genetically, it is important to ascertain the disease-causing potential of CPS1 and NAGS genetic variants. --- Explanation: Emphasizes the critical therapeutic implications of genetic diagnosis, supporting the role of genetic counseling.

[PMID:33036647] [SUPPORT] N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder --- Explanation: Autosomal recessive inheritance supports the need for genetic counseling.


MAXO:0000058

[PMID:33036647] [SUPPORT] DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. --- Explanation: Supports use of carbamylglutamate therapeutic trial for diagnosis and treatment.


hgnc:17996

[PMID:33036647] [SUPPORT] In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. --- Explanation: Documents the breadth of reported NAGS deficiency cases and families with diverse variants.

[PMID:38740568] [SUPPORT] NAGSD is cured by substitutive therapy with the N-acetyl-L-glutamate analogue N-carbamyl-L-glutamate, while curative therapy of CPS1D requires liver transplantation. Since their differentiation is done genetically, it is important to ascertain the disease-causing potential of CPS1 and NAGS genetic variants. --- Explanation: Emphasizes the critical importance of genetic characterization for differentiating NAGS deficiency from CPS1 deficiency.


MONDO:0060562

[PMID:28757203] [SUPPORT] three affected individuals from two families with severe neonatal encephalopathy --- Explanation: All reported patients presented with severe neonatal encephalopathy including hypotonia.


MONDO:0060562

[PMID:39536593] [SUPPORT] Patient had elevations in lactate (6.1 mmol/L) and glycine. --- Explanation: Fourth reported case confirms lactic acidosis as a consistent feature with quantified lactate elevation.


MONDO:0060562

[PMID:28757203] [SUPPORT] three affected individuals from two families with severe neonatal encephalopathy --- Explanation: Seizures are part of the severe neonatal encephalopathy described in the index patients.


MONDO:0060562

[PMID:28757203] [SUPPORT] Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. --- Explanation: Brain MRI in the index patients demonstrated cortical atrophy as a consistent feature.


MONDO:0060562


MONDO:0060562

[PMID:39536593] [SUPPORT] Unlike most neurometabolic disorders where dystonia develops later after metabolic stroke in basal ganglia, LIPT2-related disorder seems unique due to early onset of dystonia due to energy deficit in the developing brain. --- Explanation: The fourth reported case highlights early-onset dystonia as a distinctive feature of LIPT2 deficiency.


MONDO:0060562

[PMID:39536593] [SUPPORT] The patient was a 15-month-old female who presented at one month with dystonia, developmental delay, and feeding difficulties. --- Explanation: Developmental delay is a universal feature across all reported LIPT2 patients.


MONDO:0060562

[PMID:28757203] [SUPPORT] Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. --- Explanation: Brain MRI in index patients demonstrated white matter abnormalities as a consistent feature.


MONDO:0060562

[PMID:28757203] [SUPPORT] Plasma glycine was mildly increased. --- Explanation: Elevated glycine reflects impaired glycine cleavage system lipoylation in LIPT2 deficiency.

[PMID:39536593] [SUPPORT] Patient had elevations in lactate (6.1 mmol/L) and glycine. --- Explanation: Fourth case confirms glycine elevation as a biochemical marker of LIPT2 deficiency.


MONDO:0060562

[PMID:39536593] [SUPPORT] Brain magnetic resonance imaging showed cortical malformations including colpocephaly, polymicrogyria, and heterotopia. --- Explanation: Brain MRI in the fourth case revealed cortical malformations not previously described in LIPT2 deficiency.


MONDO:0060562

[PMID:39536593] [SUPPORT] The patient was a 15-month-old female who presented at one month with dystonia, developmental delay, and feeding difficulties. --- Explanation: Feeding difficulties reported in the fourth case.


MONDO:0060562

[PMID:28757203] [INDIRECT EVIDENCE] [SUPPORT] Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. --- Explanation: Demonstrates that LIPT2 mutations cause decreased protein lipoylation and impaired function of multiple mitochondrial enzyme complexes in patient fibroblasts.

[PMID:28757203] [INDIRECT EVIDENCE] [SUPPORT] A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. --- Explanation: Wild-type LIPT2 complementation rescues lipoylation defect, confirming LIPT2 as the causative gene.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] LIPT2 utilizes octanoyl-ACP synthesized by the mitochondrial fatty acid synthesis system to modify GCSH. --- Explanation: Review defining the biochemical role of LIPT2 as the enzyme that transfers octanoyl groups to the glycine cleavage system H protein.


MONDO:0060562

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] The loss of these two dehydrogenases short-circuits the citric acid cycle, resulting in severe respiratory deficiency and extreme muscle weakness --- Explanation: Review explaining how loss of PDHc and alpha-KGDHc disrupts the citric acid cycle and causes the clinical phenotype.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2 --- Explanation: Confirms that LIPT2 mutations affect all three lipoylated enzyme complexes.


MONDO:0060562

[PMID:28757203] [INDIRECT EVIDENCE] [SUPPORT] Plasma glycine was mildly increased. --- Explanation: Demonstrates that LIPT2 deficiency impairs the glycine cleavage system, unlike LIPT1 deficiency.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] Lack of glycine cleavage activity additionally results in elevated brain glycine levels which can result in a host of neurological disorders, including neurodegeneration, encephalopathy, and neonatal-onset epilepsy --- Explanation: Review explaining the neurological consequences of impaired glycine cleavage in lipoylation defects.


MAXO:0000950


HGNC.SYMBOL:LIPT2 loss-of-function variants

[PMID:28757203] [SUPPORT] We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. --- Explanation: Index report identifying LIPT2 as the causative gene through exome sequencing in two families.

[PMID:39536593] [SUPPORT] Exome sequencing showed two variants of uncertain significance in trans in the LIPT2 gene: c.346 G>T and c.418C>T. --- Explanation: Fourth case identifies novel LIPT2 variants confirmed by yeast complementation.

[PMID:39536593] [SUPPORT] Yeast complementation experiments indicate that both patient mutant variants result in diminished function versions of the LIPT2 protein. --- Explanation: Functional validation of novel LIPT2 variants in yeast model confirms pathogenicity.


MONDO:0060562

[PMID:28757203] [SUPPORT] We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. --- Explanation: Establishes autosomal recessive inheritance pattern with biallelic mutations in two unrelated families.


MONDO:0044923


MONDO:0044923

[PMID:40647396] [INDIRECT EVIDENCE] [SUPPORT] The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML) --- Explanation: This abstract identifies cytoplasmic NPM1 as a hallmark of NPM1-mutated AML, supporting the mislocalization mechanism.


MAXO:0000647


MAXO:0000058


CHEBI:133021


MAXO:0000747


MAXO:0000127


HGNC.SYMBOL:NPM1


MONDO:0044923

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


MONDO:0005012


MONDO:0005012

[PMID:40023845] [INDIRECT EVIDENCE] [PARTIAL] Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively. --- Explanation: This abstract reports hotspot NRAS mutations in a substantial fraction of cutaneous melanomas, supporting the NRAS-mutant subtype.


HGNC.SYMBOL:NRAS Q61R


HGNC.SYMBOL:NRAS Q61K


HGNC.SYMBOL:NRAS Q61L


MONDO:0005012

[PMID:27268913] [PARTIAL] Malignant melanoma represents a neoplasm stemming from melanocytes --- Explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.


MONDO:0700215


MONDO:0700215

[PMID:39988443] [INDIRECT EVIDENCE] [PARTIAL] Fusion variations of neurotrophic receptor tyrosine kinase (NTRK) are oncogenic drivers in various solid tumors such as breast cancer, salivary gland carcinoma, infant fibrosarcoma, etc. --- Explanation: Supports NTRK fusions as oncogenic drivers across solid tumors.


MAXO:0000058

[PMID:33258061] [SUPPORT] If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. --- Explanation: Abstract states larotrectinib can be used when NTRK fusions are detected.


NCIT:C115977

[PMID:33258061] [INDIRECT EVIDENCE] [SUPPORT] If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. --- Explanation: Abstract states larotrectinib can be used when NTRK fusions are detected.


MAXO:0000058

[PMID:33258061] [SUPPORT] If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. --- Explanation: Abstract states entrectinib can be used when NTRK fusions are detected.


CHEBI:195558

[PMID:33258061] [INDIRECT EVIDENCE] [SUPPORT] If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. --- Explanation: Abstract states entrectinib can be used when NTRK fusions are detected.


MAXO:0000058


CHEBI:229220


HGNC.SYMBOL:NTRK1

[PMID:33258061] [PARTIAL] NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. --- Explanation: Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK1 fusion involvement.


HGNC.SYMBOL:NTRK2

[PMID:33258061] [PARTIAL] NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. --- Explanation: Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK2 fusion involvement.


HGNC.SYMBOL:NTRK3

[PMID:33258061] [PARTIAL] NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. --- Explanation: Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK3 fusion involvement.


MONDO:0700215

[PMID:36914665] [SUPPORT] NTRK gene fusions are rare somatic mutations found across cancer types with --- Explanation: Abstract notes NTRK fusions occur across cancer types.


MONDO:0021107

[PMID:38077397] [SUPPORT] NT1 is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. --- Explanation: Excessive daytime sleepiness results from loss of orexin neurons that regulate wakefulness.