MONDO:0004975

[PMID:21509508] [INDIRECT EVIDENCE] [SUPPORT] Extracellular accumulations of Abeta, hyperphosphorylation of tau and intracellular neurofibrillary tangle formation have been the hallmarks of Alzheimer's Disease (AD). --- Explanation: The article discusses the role of tau hyperphosphorylation and neurofibrillary tangle formation in Alzheimer's Disease, supporting the statement about these processes.

[PMID:36001963] [INDIRECT EVIDENCE] [SUPPORT] In Alzheimer's disease and other neurodegenerative tauopathies, tau is found hyperphosphorylated and aggregated in neurofibrillary tangles. --- Explanation: This article supports the statement by mentioning the hyperphosphorylation and aggregation of tau in neurofibrillary tangles in Alzheimer's Disease.

[PMID:37266762] [INDIRECT EVIDENCE] [SUPPORT] Tau is a microtubule-associated binding protein in the nervous system that is known for its role in stabilizing microtubules throughout the nerve cell. It accumulates as beta-sheet-rich aggregates and neurofibrillary tangles, leading to an array of different pathologies. --- Explanation: The article confirms that hyperphosphorylated tau leads to the formation of neurofibrillary tangles and disrupts microtubule stabilization, supporting the statement.

[PMID:19542604] [INDIRECT EVIDENCE] [SUPPORT] Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease (AD), where it is hyperphosphorylated on serine and threonine residues. --- Explanation: This article supports the statement by identifying hyperphosphorylated tau as the main component of neurofibrillary tangles in Alzheimer's Disease.

[PMID:28100644] [INDIRECT EVIDENCE] [SUPPORT] These multicellular interactions are initiated by insoluble tangles of phosphorylated tau protein and plaques of amyloid peptides. --- Explanation: This article supports the statement by discussing how phosphorylated tau protein tangles initiate multicellular interactions in Alzheimer's Disease.

[PMID:2135393] [INDIRECT EVIDENCE] [SUPPORT] The most common of these conditions is Alzheimer's disease, in which microtubules are lost from neurites that fill up with filamentous structures. One component of the filamentous structures is the microtubule-associated protein (MAP), tau. --- Explanation: The article supports the statement by explaining how tau protein is involved in the formation of filamentous structures in Alzheimer's Disease, leading to microtubule destabilization.

[PMID:12859672] [INDIRECT EVIDENCE] [SUPPORT] Neurofibrillary tangles are composed of insoluble aggregates of the microtubule-associated protein tau. In Alzheimer's disease the accumulation of neurofibrillary tangles occurs in the absence of tau mutations. --- Explanation: This article supports the statement by describing the composition and formation of neurofibrillary tangles from tau protein in Alzheimer's Disease.

[PMID:31903881] [INDIRECT EVIDENCE] [SUPPORT] Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer's disease. --- Explanation: The article supports the statement by linking tau hyperphosphorylation and aggregation to the formation of neurofibrillary tangles in Alzheimer's Disease.

[PMID:23948895] [INDIRECT EVIDENCE] [SUPPORT] Tauopathies are neurodegenerative diseases characterized behaviorally by dementia and neuropathologically by neurofibrillary tangles and neuronal loss. --- Explanation: The article supports the statement by describing tauopathies, including Alzheimer's Disease, as being characterized by neurofibrillary tangles and neuronal loss.


MONDO:0004975


MONDO:0004975

[PMID:27662312] [INDIRECT EVIDENCE] [SUPPORT] Compelling evidence suggests that soluble amyloid-beta (Abeta) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). --- Explanation: The statement is supported by the reference which discusses the role of neurotransmitter release and synaptic plasticity in Alzheimer's Disease, leading to cognitive decline.

[PMID:27163751] [INDIRECT EVIDENCE] [PARTIAL] The important role of the hippocampus in age-related cognitive decline and in vulnerability to disease processes such as Alzheimer's disease has prompted this review, which will focus on the complexity of changes that characterize aging, and on the molecular connections that exist between normal aging and Alzheimer's disease. --- Explanation: The reference supports the cognitive decline aspect but does not elaborate on neurotransmitter signaling or synaptic plasticity in detail.

[PMID:12973746] [INDIRECT EVIDENCE] [SUPPORT] Histological studies indicate loss of pyramidal neurones and their synapses in Alzheimer's disease (AD), this together with biochemical evidence suggests presynaptic (and postsynaptic) glutamatergic hypoactivity. --- Explanation: The reference supports the statement by discussing the loss of synapses and impaired glutamatergic neurotransmitter signaling in Alzheimer's Disease.

[PMID:33232936] [INDIRECT EVIDENCE] [SUPPORT] In the present study, we examined alterations in several GABA-specific targets in the APP/PS1 mouse model at different ages... Overall, our study provides evidence of altered GABAergic signaling in an amyloid model of AD at a time point consistent with AD-related deficits. --- Explanation: The reference supports the statement by providing evidence of altered GABAergic signaling and its role in Alzheimer's Disease.

[PMID:9024330] [INDIRECT EVIDENCE] [SUPPORT] The major component of the extraneuronal neuritic plaque is beta-amyloid (A beta), which may be neurotoxic. The major component of the intraneuronal neurofibrillary tangle is hyperphosphorylated tau protein. --- Explanation: The reference supports the statement by discussing neurotoxic components that contribute to synaptic dysfunction and cognitive decline in Alzheimer's Disease.


MONDO:0004975

[PMID:28019679] [INDIRECT EVIDENCE] [SUPPORT] NOD-like receptor (NLR) family, pyrin domain containing 3 and 1 inflammasomes, present in myeloid cells and neurons, respectively, represent key components of the innate immune reaction observed in Alzheimer patient brains. --- Explanation: The reference supports the involvement of NLRP3 inflammasome activation in Alzheimer's disease, which is part of the immune activation process contributing to neuroinflammation.

[PMID:32061803] [INDIRECT EVIDENCE] [SUPPORT] The response of astrocytes to the presence of Abeta, as well astrocytic and microglial interaction and inflammatory cytokine release is also discussed, highlighting a cyclical behaviour of these cells in contributing to AD pathogenesis. --- Explanation: This reference supports the role of astrocytes and microglia in cytokine production and their interaction contributing to Alzheimer's disease pathology.

[PMID:35406803] [INDIRECT EVIDENCE] [SUPPORT] Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators. --- Explanation: This reference supports the involvement of microglia in immune activation, cytokine production, and phagocytosis in Alzheimer's disease.

[PMID:21546088] [INDIRECT EVIDENCE] [SUPPORT] In age related diseases, such as Alzheimer's disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. --- Explanation: This reference supports the involvement of complement proteins, cytokines, and oxidative stress in Alzheimer's disease.

[PMID:23930978] [INDIRECT EVIDENCE] [SUPPORT] A vicious cycle of inflammation has been formed between Abeta accumulation, activated microglia, and microglial inflammatory mediators, which enhance Abeta deposition and neuroinflammation. --- Explanation: Review of microglia dual roles in AD pathogenesis, describing the vicious cycle between Aβ accumulation, microglial activation, and inflammatory mediator release.

[PMID:36357946] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, exposure to chronic stress alters the phenotype of microglia, a population of innate immune cells that reside in the CNS parenchyma. --- Explanation: This reference supports the role of microglia as key players in immune activation and neuroinflammation.


MONDO:0004975

[PMID:34416493] [INDIRECT EVIDENCE] [SUPPORT] Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). --- Explanation: The literature supports the role of oxidative stress, including the imbalance between ROS production and antioxidant defenses, in the development of Alzheimer's disease.

[PMID:27888001] [INDIRECT EVIDENCE] [SUPPORT] Depending on its level, HNE exerts harmful or protective effects associated with the induction of antioxidant defense mechanisms. These effects make HNE a key player in maintaining redox homeostasis, as well as producing imbalances in this system that participate in aging and the development of pathological conditions. --- Explanation: This reference supports the involvement of oxidative stress and the imbalance in ROS/RNS in the pathology of neurodegenerative diseases.

[PMID:9024330] [INDIRECT EVIDENCE] [PARTIAL] Although the specific process that destroys neurons in patients with Alzheimer's disease (AD) remains obscure, biochemical studies of AD neurohistologic lesions and molecular attempts to map and clone genes in familial AD have contributed greatly to our knowledge of AD. --- Explanation: This reference discusses the uncertainty around the specific processes but acknowledges oxidative stress as a contributing factor.

[PMID:25772897] [INDIRECT EVIDENCE] [PARTIAL] Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. --- Explanation: This reference supports the involvement of oxidative stress and mitochondrial damage in neurodegeneration but does not specifically focus on Alzheimer's disease.

[PMID:33164705] [INDIRECT EVIDENCE] [SUPPORT] Oxidative stress-induced neuronal apoptosis plays a pivotal role in pathogenesis of neurodegeneration. --- Explanation: This reference supports the role of oxidative stress in neurodegeneration, which is relevant to Alzheimer's disease.


MONDO:0004975

[PMID:28902142] [INDIRECT EVIDENCE] [SUPPORT] Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Abeta accumulation and neurovascular unit impairments during disease progression. --- Explanation: This reference supports the statement by indicating that blood-brain barrier (BBB) dysfunction contributes to Alzheimer's disease (AD) pathogenesis, including amyloid-beta (Abeta) accumulation and neurovascular impairments.

[PMID:16443487] [INDIRECT EVIDENCE] [SUPPORT] Understanding cerebral degeneration and accumulation of beta-amyloid has generated hopes for discovery of disease-modifying treatments. Progress is needed in understanding the mechanisms that link beta-amyloid accumulation and neuronal death. --- Explanation: This reference supports the statement by discussing the accumulation of beta-amyloid and its link to neuronal death in Alzheimer's disease, which is relevant to the described consequences of vascular dysfunction.

[PMID:26898552] [INDIRECT EVIDENCE] [SUPPORT] There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer's disease (AD), perhaps even before amyloid-beta accumulation or brain atrophy. --- Explanation: This reference supports the statement by highlighting the role of cerebral blood flow changes in the early stages of Alzheimer's disease, which is consistent with the described vascular dysfunction.

[PMID:36293539] [INDIRECT EVIDENCE] [SUPPORT] Aberrant remodeling of microvesselsis associated with blood-brain barrier breakdown, development of neuroinflammation, inadequate microcirculation in active brain regions, and leads to the dysfunction of the neurovascular unit and progressive neurological deficits. --- Explanation: This reference supports the statement by describing how microvascular remodeling and blood-brain barrier breakdown contribute to neurovascular unit dysfunction and neurological deficits, relevant to Alzheimer's disease.

[PMID:35289012] [INDIRECT EVIDENCE] [SUPPORT] We consider how abnormalities of the constituent cells of the neurovascular unit - particularly of endothelial cells and pericytes - and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD. --- Explanation: This reference supports the statement by discussing the role of endothelial cells and pericytes in blood-brain barrier impairment and Alzheimer's disease pathogenesis.


MAXO:0000058

[PMID:24807367] [SUPPORT] Donepezil, galantamine and rivastigmine are commonly used AChEIs in pharmacotherapy for AD, slowing the progression and controlling the symptoms of AD. --- Explanation: The literature supports that cholinesterase inhibitors, including donepezil and rivastigmine, are used to help with symptoms of Alzheimer's disease by slowing the progression and controlling cognitive symptoms.

[PMID:28671413] [SUPPORT] Cholinesterase inhibitors, memantine, and a combination of a cholinesterase inhibitor and memantine have produced statistically significant but clinically small delays in various domains of cognitive and functional decline in select patients with Alzheimer disease. --- Explanation: The literature supports the use of cholinesterase inhibitors in delaying cognitive decline in Alzheimer's disease.

[PMID:35608903] [SUPPORT] Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer''s disease. --- Explanation: The literature confirms that cholinesterase inhibitors are licensed for use in Alzheimer's disease to alleviate symptoms and delay disease progression.

[PMID:36412156] [SUPPORT] Currently approved medications are symptomatic and include two classes: cholinesterase inhibitors, such as donepezil, and NMDA receptor antagonist memantine. --- Explanation: The literature supports that cholinesterase inhibitors are approved symptomatic treatments for Alzheimer's disease.

[PMID:9108896] [SUPPORT] Donepezil is a specific and potent acetylcholinesterase inhibitor... Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function. --- Explanation: The literature supports that donepezil, a cholinesterase inhibitor, helps improve cognitive function in Alzheimer's disease.


MAXO:0000058

[PMID:12768511] [SUPPORT] Memantine, an antagonist of the glutamatergic NMDA receptor, has been recently approved for the treatment of advanced AD. Due to its action mechanism, memantine is considered a neuroprotective drug, whose utility has been demonstrated in preclinical studies, and a useful symptomatic treatment for AD and vascular dementia. --- Explanation: The abstract confirms that memantine, an NMDA receptor antagonist, is used to treat Alzheimer's Disease by regulating glutamate activity.

[PMID:27662322] [SUPPORT] Studies indicate that the distinct outcomes of NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs promotes cell death and thus contributes to the etiology of AD, which can be blocked by an AD drug, memantine, an NMDAR antagonist that selectively blocks the function of extrasynaptic NMDARs. --- Explanation: This abstract highlights that memantine, an NMDA receptor antagonist, helps in blocking the negative effects of excessive NMDAR activity in Alzheimer's Disease.

[PMID:20943326] [SUPPORT] The hypothesis proposed is restoration of medium spiny neurons in Huntington's disease using neural progenitor cell implantation and attenuation of glutamate mediated excitotoxicity using a partial glutamate antagonist - Memantine. Memantine can block the NMDA receptors and will prevent excess calcium influx into the neurons decreases the vulnerability of medium spiny neurons to glutamate mediated excitotoxicity. --- Explanation: Although primarily discussing Huntington's Disease, this abstract supports the idea that memantine, an NMDA receptor antagonist, regulates glutamate activity, which is relevant to Alzheimer's Disease treatment.


MAXO:0000077

[PMID:35621327] [SUPPORT] Cognitive stimulation was found to be an effective intervention for people with moderate Alzheimer's disease because it helped to maintain memory function, executive functions, and attention. --- Explanation: This study specifically highlights the effectiveness of cognitive stimulation in maintaining cognitive functions in patients with moderate Alzheimer's disease.

[PMID:28671413] [SUPPORT] Cognitive stimulation programs show benefit in maintenance of cognitive function and improved self-reported quality of life in patients with mild to moderate Alzheimer disease. --- Explanation: This reference supports the statement by indicating that cognitive stimulation programs help maintain cognitive function in patients with mild to moderate Alzheimer's disease.

[PMID:37428401] [PARTIAL] CS confers temporary, nonspecific benefits and might slightly reduce dementia risk for neurologically healthy individuals. --- Explanation: This reference indicates that cognitive stimulation offers temporary benefits and might reduce dementia risk, but it is less clear about long-term maintenance of cognitive function specifically in Alzheimer's disease.

[PMID:21643921] [PARTIAL] Mental training and cognitive stimulation interventions in AD have been shown to be useful in increasing patients' ability in performing activities of daily living (ADL), allowing them to maintain relative independence. --- Explanation: This reference supports the utility of cognitive interventions in maintaining daily functioning, which is related to cognitive function, but does not directly address cognitive maintenance alone.

[PMID:27159433] [SUPPORT] Interventions involving physical exercise and cognitive training have consistently shown positive effects on cognition in older adults. --- Explanation: This reference supports the statement by indicating that cognitive training, a form of cognitive therapy, has positive effects on cognition in older adults, including those with Alzheimer's disease.


MAXO:0000950

[PMID:28809650] [SUPPORT] Occupational therapy practitioners play a significant role in supporting adults with Alzheimer's disease and related major neurocognitive disorders, as well as their caregivers, through all phases of the disease process. --- Explanation: The reference highlights the role of occupational therapy in supporting individuals with Alzheimer's disease, which aligns with the statement that includes occupational therapy as part of supportive care.

[PMID:38883339] [SUPPORT] The telephone hotline is a useful component of dementia care in Germany and an important contribution to the National Dementia Strategy. --- Explanation: The reference discusses the importance of caregiver support through telephone counseling, aligning with the statement that includes caregiver support as part of supportive care.

[PMID:29361068] [SUPPORT] This article first describes the educational, information, and support needs of individuals living dementia and their family caregivers across all stages of Alzheimer's. --- Explanation: The reference discusses the support needs of individuals with Alzheimer's disease and their caregivers, which aligns with the statement that includes caregiver support as part of supportive care.

[PMID:27651009] [PARTIAL] Cholinesterase inhibitors and memantine are used from 15 years, in Alzheimer's disease. Benefits have been demonstrated according to cognition, activities of daily living, affective symptoms and behavior, and global impression of change. --- Explanation: The reference primarily discusses pharmacological treatments, with some mention of activities of daily living, but does not specifically address occupational therapy or speech therapy.


MAXO:0000088

[PMID:35503939] [SUPPORT] The aim of this review is to emphasize the importance of mental activity and aerobic physical exercise as one of the most important health-related activities which may delay the onset or slow down the progression of Alzheimer's dementia. --- Explanation: The review highlights the importance of mental and physical exercise in potentially slowing the progression of Alzheimer's disease.

[PMID:32579499] [SUPPORT] Combined with the prevention of AD risk factors such as heart disease, diabetes, and with more recent evidence, microbiome dysfunction, there is a substantial foundation for diet as a modifiable risk factor and preventative measure for AD. --- Explanation: The review suggests that a healthy diet can be a preventative measure for Alzheimer's disease, supporting the role of lifestyle modifications.

[PMID:37321363] [SUPPORT] Results showed that eating a healthy diet with plenty of fruits and vegetables, and participation in leisure and physical activities may protect against cognitive decline and cognitive impairment among oldest-old regardless of the APOE genotype. --- Explanation: The systematic review indicates that lifestyle factors such as diet and physical activities may protect against cognitive decline, supporting the statement.

[PMID:38129775] [SUPPORT] Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health. --- Explanation: The intervention described combines lifestyle modifications and memory support to improve cognitive health, supporting the statement.


HGNC.SYMBOL:APP

[PMID:1365885] [SUPPORT] Four mutations involving amino acid substitutions in exons 16 and 17 of the amyloid precursor protein (APP) gene, have been identified which co-segregate with the disease in some families multiply affected by early onset Alzheimer's disease. --- Explanation: This reference supports the association of APP genetic mutations with early-onset Alzheimer's disease.

[PMID:33789815] [SUPPORT] This is the first case demonstrating that a low-degree APP gene-dose increase suffices to cause EOAD with prominent amyloid-beta/tau pathology. --- Explanation: This reference supports the role of APP gene mutations in causing early-onset Alzheimer's disease.

[PMID:36306459] [SUPPORT] Numerous mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been identified for EOAD, but they can only account for a small proportion of EOAD cases. --- Explanation: This reference supports the association of APP genetic mutations with early-onset Alzheimer's disease.

[PMID:31623876] [SUPPORT] In this study, a novel mutation in APP gene, Val669Leu ('Seoul APP'), was reported in a Korean female patient with Alzheimer's disease. --- Explanation: This reference supports the association of APP genetic mutations with early-onset Alzheimer's disease.

[PMID:26243569] [SUPPORT] It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor. --- Explanation: This reference supports the association of APP genetic mutations with early-onset Alzheimer's disease.

[PMID:22727994] [SUPPORT] APP mutations cause Alzheimer disease (AD) with virtually complete penetrance. --- Explanation: This reference supports the association of APP genetic mutations with early-onset Alzheimer's disease.


HGNC.SYMBOL:PSEN1

[PMID:31296348] [SUPPORT] Presenilin 1 (PSEN1) gene mutations are the major known genetic cause of early-onset Alzheimer's disease. --- Explanation: The study reports a novel PSEN1 mutation associated with early-onset Alzheimer's disease, supporting the genetic association.

[PMID:35487021] [SUPPORT] At present, three early-onset AD genes (APP, PSEN1, PSEN2) and one late-onset AD susceptibility gene apolipoprotein E (APOE) have been determined. --- Explanation: The reference confirms that PSEN1 is one of the genes associated with early-onset Alzheimer's disease.

[PMID:36951251] [SUPPORT] A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation. --- Explanation: The study discusses a large cohort with a specific PSEN1 mutation associated with early-onset Alzheimer's disease, reinforcing the genetic link.

[PMID:36641620] [SUPPORT] Early-onset AD represents about 5.5% of the total cases and occurs in patients under age 65. The EOAD progresses more aggressively and has a shorter life expectancy due to a greater pathogenic load. --- Explanation: The reference discusses early-onset Alzheimer's disease and mentions PSEN1 mutations, supporting the genetic association.

[PMID:35430993] [SUPPORT] Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5-10% of all Alzheimer's disease (AD) cases. --- Explanation: The study highlights the occurrence of early-onset Alzheimer's disease and mentions PSEN1 mutations, supporting the genetic link.

[PMID:30549411] [SUPPORT] The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. --- Explanation: The reference confirms that PSEN1 mutations are a frequent cause of early-onset Alzheimer's disease.


HGNC.SYMBOL:PSEN2

[PMID:35491795] [SUPPORT] The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%, Alzheimer''s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. --- Explanation: The reference confirms that PSEN2 mutations are among the causative factors for early-onset Alzheimer's disease.

[PMID:36701017] [SUPPORT] Early-onset AD (EOAD) was defined as AD occurring before age 65. Although it has a high genetic risk, EOAD due to PSEN2 variation is very rare. --- Explanation: The reference supports the association of PSEN2 with early-onset Alzheimer's disease, although it notes that such cases are rare.

[PMID:32741831] [SUPPORT] Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. --- Explanation: The reference explicitly states that early-onset familial Alzheimer's disease can be caused by PSEN2 mutations.


HGNC.SYMBOL:APOE


HGNC.SYMBOL:TREM2


HGNC.SYMBOL:NLRP3


HGNC.SYMBOL:PYCARD


HGNC.SYMBOL:LRP1


MONDO:0004976

[PMID:31871139] [NO_EVIDENCE] motor neuron disease (MND) --- Explanation: Study of motor neuron disease patients confirms muscle weakness as a defining feature.


MONDO:0004976

[PMID:27117334] [SUPPORT] In the LMN system, fasciculation potentials (FPs) are the earliest changes observed in affected muscles, a feature of LMN hyperexcitability. --- Explanation: Review confirms fasciculations are an early marker of lower motor neuron dysfunction in ALS.


MONDO:0004976

[PMID:33085325] [SUPPORT] Upper motor findings include spasticity, hyperactive reflexes, and a positive Babinski sign. --- Explanation: StatPearls article confirms spasticity as a cardinal upper motor neuron sign in ALS.


MONDO:0004976

[PMID:33085325] [SUPPORT] Upper motor findings include spasticity, hyperactive reflexes, and a positive Babinski sign. --- Explanation: StatPearls motor neuron disease review lists hyperactive reflexes as a core upper motor neuron finding in ALS.


MONDO:0004976

[PMID:33085325] [SUPPORT] Bulbar dysfunction can manifest as dysphagia (trouble swallowing) and dysarthria (trouble speaking). --- Explanation: Review notes bulbar dysfunction in ALS commonly presents with dysarthria and dysphagia.


MONDO:0004976

[PMID:33085325] [SUPPORT] Bulbar dysfunction can manifest as dysphagia (trouble swallowing) and dysarthria (trouble speaking). --- Explanation: StatPearls article highlights dysphagia as a common bulbar manifestation in ALS.

[PMID:39207520] [SUPPORT] Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. --- Explanation: Dysphagia-focused review reports that swallowing difficulty affects the majority of ALS patients and requires routine assessment.


MONDO:0004976

[PMID:33085325] [SUPPORT] Death usually occurs within 2 to 5 years from respiratory failure. --- Explanation: Clinical overview states respiratory failure is the usual terminal event in ALS.


MONDO:0004976

[PMID:33085325] [SUPPORT] Lower motor neuron signs include muscle atrophy, weakness, flaccid paralysis, absent reflexes, fasciculations, and fibrillations. --- Explanation: Review details muscle atrophy as a key lower motor neuron sign in ALS.


MONDO:0004976

[PMID:38521060] [INDIRECT EVIDENCE] [PARTIAL] Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features --- Explanation: Single-cell analysis confirms motor neuron vulnerability in ALS and identifies vulnerable populations in cortical layer 5.

[PMID:38891021] [INDIRECT EVIDENCE] [SUPPORT] upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. --- Explanation: Review summarizes canonical ALS pathology of progressive upper and lower motor neuron degeneration causing loss of voluntary movement.

[PMID:36116464] [INDIRECT EVIDENCE] [PARTIAL] Amyotrophic lateral sclerosis is a fatal CNS neurodegenerative disease. --- Explanation: Lancet Seminar underscores ALS as a fatal neurodegenerative disorder affecting central nervous system motor pathways.


MONDO:0004976


MONDO:0004976

[PMID:16736722] [INDIRECT EVIDENCE] [PARTIAL] the most common tau negative ubiquitin positive amyotrophic lateral sclerosis (ALS) type inclusions --- Explanation: Review confirms ubiquitin-positive inclusions as a common pathological feature in ALS.


MONDO:0004976

[PMID:8302340] [INDIRECT EVIDENCE] [PARTIAL] Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. --- Explanation: Trial of riluzole, an antiglutamate agent, supports role of glutamate excitotoxicity in ALS pathogenesis.

[PMID:40508048] [INDIRECT EVIDENCE] [SUPPORT] understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. --- Explanation: Recent mechanistic review highlights glutamate-mediated excitotoxicity as a key pathogenic process and therapeutic target in ALS.


MONDO:0004976

[PMID:8446170] [INDIRECT EVIDENCE] [SUPPORT] a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion --- Explanation: Discovery of SOD1 mutations in familial ALS implicates oxidative stress in disease pathogenesis.

[PMID:40508048] [INDIRECT EVIDENCE] [SUPPORT] This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy. --- Explanation: Review emphasizes oxidative stress as a targetable pathogenic mechanism and discusses antioxidant therapeutic strategies in ALS.

[PMID:35269543] [INDIRECT EVIDENCE] [SUPPORT] ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. --- Explanation: Therapeutic strategies review highlights oxidative stress among key pathological mechanisms contributing to ALS.


MONDO:0004976

[PMID:34440810] [INDIRECT EVIDENCE] [PARTIAL] In the archetypical neurodegenerative disorder amyotrophic lateral sclerosis (ALS), the recruitment of T-cells is well known --- Explanation: Review confirms immune cell involvement in ALS pathophysiology with T-cell recruitment to affected areas.


MONDO:0004976

[PMID:34874625] [INDIRECT EVIDENCE] [SUPPORT] Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. --- Explanation: Review summarizes how microglial TREM2 function shapes ALS progression and highlights its role in microglial activation.


MONDO:0004976

[PMID:22312314] [INDIRECT EVIDENCE] [PARTIAL] Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). --- Explanation: Review confirms axonal transport defects as early pathogenic events in ALS.


MONDO:0004976

[PMID:28148298] [INDIRECT EVIDENCE] [SUPPORT] TBK1 also has a major role in autophagy and mitophagy, chiefly the phosphorylation of autophagy adaptors. Several other ALS genes are also involved in autophagy, including p62 and OPTN. --- Explanation: Review describes TBK1's role in autophagy and confirms multiple ALS genes function in autophagy pathways.


MAXO:0000058

[PMID:8302340] [SUPPORT] The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset. --- Explanation: Landmark trial demonstrating riluzole's survival benefit in ALS patients.


NCIT:C47704

[PMID:8302340] [INDIRECT EVIDENCE] [SUPPORT] The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset. --- Explanation: Landmark trial demonstrating riluzole's survival benefit in ALS patients.


MAXO:0000058

[PMID:28522181] [SUPPORT] Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. --- Explanation: Phase 3 trial demonstrating edaravone slows functional decline in early-stage ALS patients.

[PMID:35006266] [REFUTE] although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. --- Explanation: Real-world cohort study found long-term intravenous edaravone well tolerated but without additional disease-modifying benefit versus standard therapy.


CHEBI:31530

[PMID:28522181] [INDIRECT EVIDENCE] [SUPPORT] Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. --- Explanation: Phase 3 trial demonstrating edaravone slows functional decline in early-stage ALS patients.

[PMID:35006266] [INDIRECT EVIDENCE] [REFUTE] although long-term intravenous edaravone therapy for patients with ALS was feasible and mainly well tolerated, it was not associated with any disease-modifying benefit. --- Explanation: Real-world cohort study found long-term intravenous edaravone well tolerated but without additional disease-modifying benefit versus standard therapy.


MAXO:0000058

[PMID:32640130] [SUPPORT] In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. --- Explanation: Phase 1-2 trial demonstrating tofersen reduces CSF SOD1 levels in SOD1-ALS patients.


NCIT:C166584

[PMID:32640130] [INDIRECT EVIDENCE] [SUPPORT] In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. --- Explanation: Phase 1-2 trial demonstrating tofersen reduces CSF SOD1 levels in SOD1-ALS patients.


MAXO:0000506

[PMID:16426990] [SUPPORT] This subgroup showed improvement in several measures of quality of life and a median survival benefit of 205 days (p=0.006) with maintained quality of life for most of this period. --- Explanation: Randomized controlled trial demonstrated non-invasive ventilation improves quality of life and extends survival in ALS patients with preserved bulbar function.


MAXO:0000011

[PMID:24510737] [SUPPORT] Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. --- Explanation: Review describes how rehabilitation including physical therapy helps maximize independence and function in ALS patients.


MAXO:0000930

[PMID:24510737] [SUPPORT] This review will present rehabilitation strategies that can be utilized to maximize patient independence, function, safety, and quality of life, and to minimize disease-related symptoms. --- Explanation: Review covers multidisciplinary rehabilitation including speech therapy for ALS patients.


MAXO:0000950

[PMID:39207520] [SUPPORT] Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. --- Explanation: Dysphagia management review underscores PEG as an essential intervention when nutrition is compromised in ALS.


MAXO:0000950

[PMID:24510737] [SUPPORT] Multidisciplinary care includes rehabilitation interventions that have the goal of assisting people to teach their fullest potential despite the presence of a disabling disease. --- Explanation: Rehabilitation review emphasizes multidisciplinary care as core to ALS management to optimize function and quality of life.


HGNC.SYMBOL:C9orf72 Repeat Expansion

[PMID:21944778] [SUPPORT] Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%) --- Explanation: Original discovery paper establishing C9orf72 as the most common genetic cause of familial ALS.


HGNC.SYMBOL:SOD1 Mutations

[PMID:8446170] [SUPPORT] We identified 11 different SOD1 missense mutations in 13 different FALS families. --- Explanation: Original discovery paper identifying SOD1 mutations as a cause of familial ALS.


HGNC.SYMBOL:TARDBP Mutations

[PMID:35805149] [SUPPORT] Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. --- Explanation: Gene therapy review highlights TARDBP among the most common ALS genes targeted by therapeutic strategies.


HGNC.SYMBOL:FUS Mutations

[PMID:35805149] [SUPPORT] Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. --- Explanation: Review notes FUS among the four most common ALS genes and discusses gene-targeted therapies.


HGNC.SYMBOL:NEK1 Variants

[PMID:27455347] [SUPPORT] In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. --- Explanation: Large-scale genetic study identifying NEK1 variants as risk factors for ALS.


MONDO:0007113

[PMID:20301323] [SUPPORT] Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability --- Explanation: Supports severe cognitive impairment as a core phenotype.


MONDO:0007113

[PMID:14510623] [SUPPORT] Clinical findings present in all patients include developmental delay, which becomes apparent by 6-12 months of age --- Explanation: Supports near-universal developmental delay and its timing.


MONDO:0007113

[PMID:14510623] [SUPPORT] Clinical findings present in all patients include developmental delay, which becomes apparent by 6-12 months of age, severely impaired expressive language --- Explanation: Supports severe expressive language impairment as a defining feature.


MONDO:0007113

[PMID:20301323] [SUPPORT] Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs --- Explanation: Supports ataxic gait as a cardinal motor phenotype.


MONDO:0007113

[PMID:20398390] [SUPPORT] Epilepsy, often severe and hard to control, is present in 85% of patients within the first three years of life, although less than 25% develop seizures during the first year. --- Explanation: Quantifies high seizure prevalence and early onset.


MONDO:0007113

[PMID:24876791] [SUPPORT] The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. --- Explanation: Supports sleep disturbance as a recurring syndrome feature.


MONDO:0007113

[PMID:14510623] [SUPPORT] Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% of patients. --- Explanation: Supports very high prevalence of microcephaly.


MONDO:0007113

[PMID:14510623] [SUPPORT] Clinical findings present in all patients include developmental delay, which becomes apparent by 6-12 months of age, severely impaired expressive language, ataxic gait, tremulousness of limbs, and a typical behavioral profile, including a happy demeanor, hypermotoric behavior, and low attention span. --- Explanation: Supports hypermotor/hyperactive behavioral phenotype.


MONDO:0007113

[PMID:20398390] [SUPPORT] Angelman syndrome (AS) is a neuro-behavioural, genetically determined condition, characterized by ataxic jerky movements, happy sociable disposition and unprovoked bouts of laughter in association with seizures, learning disabilities and language impairment. --- Explanation: Supports characteristic laughter/happy demeanor phenotype.


MONDO:0007113

[PMID:28816003] [SUPPORT] The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. --- Explanation: Supports constipation as one of the most prevalent GI comorbidities.


MONDO:0007113

[PMID:28816003] [SUPPORT] The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. --- Explanation: Supports GERD as a major GI phenotype in AS.


MONDO:0007113

[PMID:14510623] [SUPPORT] Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% of patients. --- Explanation: Supports scoliosis as a common and clinically relevant musculoskeletal manifestation.


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. --- Explanation: Establishes the initiating molecular lesion.


MONDO:0007113


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] in neurons only the maternally inherited UBE3A gene is expressed. --- Explanation: Supports neuron-specific imprinting mechanism.


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] Angelman syndrome is caused by the loss of UBE3A protein. --- Explanation: Supports this discrete protein-abundance event.

[PMID:40671377] [INDIRECT EVIDENCE] [SUPPORT] AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). --- Explanation: Human iPSC-derived cortical-neuron study provides direct molecular support linking neuronal UBE3A loss to altered ubiquitin-dependent protein regulation.


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] Loss of UBE3A affects multiple signalling pathways in the brain. --- Explanation: Supports broad neuronal signaling dysregulation downstream of reduced ubiquitination control.

[PMID:40671377] [INDIRECT EVIDENCE] [SUPPORT] We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS. --- Explanation: Adds direct mechanistic evidence that UBE3A-dependent ubiquitination regulates neuronal protein turnover linked to synaptic dysfunction.


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. --- Explanation: Supports multipathway dysregulation framing.


MONDO:0007113

[PMID:24876791] [INDIRECT EVIDENCE] [SUPPORT] Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling. --- Explanation: Supports this discrete synaptic-remodeling event.

[PMID:36237484] [INDIRECT EVIDENCE] [SUPPORT] Like in male AS mice, long-term potentiation (LTP) was significantly reduced while long-term depression (LTD) was enhanced at hippocampal CA3-CA1 synapses of female AS mice, as compared to female WT mice. --- Explanation: Provides synapse-level electrophysiologic evidence for impaired plasticity in Angelman model systems.

[PMID:40310720] [INDIRECT EVIDENCE] [SUPPORT] Moreover, deficits in mEPSC frequency and spike-timing-dependent long-term potentiation, as well as certain behaviors including cognitive inflexibility found in AS mice, are rescued when bred with Kv4.2 conditional knockout mice. --- Explanation: Supports causal linkage between UBE3A downstream signaling defects and synaptic plasticity abnormalities.


MONDO:0007113

[PMID:33543479] [INDIRECT EVIDENCE] [SUPPORT] It has been consistently shown that mouse models of Angelman syndrome show marked changes in synaptic plasticity and excitatory/inhibitory balance. --- Explanation: Supports disrupted excitability homeostasis event.

[PMID:39914145] [INDIRECT EVIDENCE] [SUPPORT] The axon initial segment (AIS) is a critical regulator of neuronal excitability and the initiation site of action potentials. --- Explanation: Adds direct mechanistic support for excitability-homeostasis framing in cortical neurons.


MONDO:0007113

[PMID:14510623] [INDIRECT EVIDENCE] [SUPPORT] Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% of patients. --- Explanation: Supports coupling of epileptic burden with abnormal EEG background.


MAXO:0000058

[PMID:27206232] [SUPPORT] Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. --- Explanation: Supports use of specific newer ASMs with improved tolerability in Angelman syndrome.

[PMID:35862628] [PARTIAL] Evidence for treating seizures in AS mainly derives from low-quality studies. Levetiracetam and clobazam are the most commonly used ASMs. --- Explanation: Adds review-level context on current ASM usage patterns and evidence limitations.

[PMID:20301323] [SUPPORT] Treatment of manifestations: Anti-seizure medication for seizures. --- Explanation: Direct management recommendation for epilepsy in AS.


CHEBI:6437

[PMID:27206232] [INDIRECT EVIDENCE] [SUPPORT] Newer antiepileptic drugs such as levetiracetam, lamotrigine, and clobazam, and to a lesser extent topiramate, appeared to be as effective - if not more so - as valproic acid and clonazepam while offering more favorable side effect profiles. --- Explanation: Supports use of specific newer ASMs with improved tolerability in Angelman syndrome.

[PMID:35862628] [INDIRECT EVIDENCE] [PARTIAL] Evidence for treating seizures in AS mainly derives from low-quality studies. Levetiracetam and clobazam are the most commonly used ASMs. --- Explanation: Adds review-level context on current ASM usage patterns and evidence limitations.

[PMID:20301323] [INDIRECT EVIDENCE] [SUPPORT] Treatment of manifestations: Anti-seizure medication for seizures. --- Explanation: Direct management recommendation for epilepsy in AS.


CHEBI:6367


CHEBI:31413


CHEBI:39867


MAXO:0000058


MAXO:0000088

[PMID:27206232] [SUPPORT] The low glycemic index treatment also provided effective seizure control with minimal side effects. --- Explanation: Supports LGIT as an adjunctive dietary option for seizure control.

[PMID:41121232] [PARTIAL] INTERPRETATION: While the LGID was well-tolerated and showed trends toward neurocognitive and seizure improvements, results were not statistically significant. --- Explanation: Adds contemporary prospective evidence showing tolerability with non-significant efficacy trends.


MAXO:0000088

[PMID:27206232] [INDIRECT EVIDENCE] [SUPPORT] The low glycemic index treatment also provided effective seizure control with minimal side effects. --- Explanation: Supports LGIT as an adjunctive dietary option for seizure control.

[PMID:41121232] [INDIRECT EVIDENCE] [PARTIAL] INTERPRETATION: While the LGID was well-tolerated and showed trends toward neurocognitive and seizure improvements, results were not statistically significant. --- Explanation: Adds contemporary prospective evidence showing tolerability with non-significant efficacy trends.


MAXO:0000088


MAXO:0001081

[PMID:40776598] [SUPPORT] Twelve children with Angelman syndrome underwent tonsillectomy: 7 for sleep-disordered breathing, 4 for sialorrhea, and 1 for recurrent tonsillitis. --- Explanation: Supports procedure-level use of tonsillectomy for specific clinical indications in Angelman syndrome.

[PMID:40776598] [SUPPORT] Nine (75.0%) children experienced postoperative complications, most frequently pooling of secretions and oxygen desaturations. --- Explanation: Supports need for enhanced perioperative and postoperative monitoring after tonsillectomy.


MAXO:0001081

[PMID:40776598] [INDIRECT EVIDENCE] [SUPPORT] Twelve children with Angelman syndrome underwent tonsillectomy: 7 for sleep-disordered breathing, 4 for sialorrhea, and 1 for recurrent tonsillitis. --- Explanation: Supports procedure-level use of tonsillectomy for specific clinical indications in Angelman syndrome.

[PMID:40776598] [INDIRECT EVIDENCE] [SUPPORT] Nine (75.0%) children experienced postoperative complications, most frequently pooling of secretions and oxygen desaturations. --- Explanation: Supports need for enhanced perioperative and postoperative monitoring after tonsillectomy.


MAXO:0001081


MAXO:0000011

[PMID:20301323] [SUPPORT] Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. --- Explanation: Supports standard multidisciplinary rehabilitative care.


MAXO:0000011

[PMID:20301323] [INDIRECT EVIDENCE] [SUPPORT] Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. --- Explanation: Supports standard multidisciplinary rehabilitative care.


MAXO:0001351

[PMID:20301323] [SUPPORT] Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. --- Explanation: Supports occupational therapy as part of standard multidisciplinary care.


MAXO:0000930

[PMID:20301323] [SUPPORT] Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. --- Explanation: Supports speech-language intervention tailored to severe expressive impairment.


MAXO:0000930

[PMID:20301323] [INDIRECT EVIDENCE] [SUPPORT] Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards, communication boards) and signing. --- Explanation: Supports speech-language intervention tailored to severe expressive impairment.


MAXO:0000950

[PMID:20301323] [SUPPORT] Routine management of gastroesophageal reflux, feeding difficulties, constipation, and strabismus. --- Explanation: Supports routine GI-focused symptomatic management.


MAXO:0000950

[PMID:20301323] [INDIRECT EVIDENCE] [SUPPORT] Routine management of gastroesophageal reflux, feeding difficulties, constipation, and strabismus. --- Explanation: Supports routine GI-focused symptomatic management.


MAXO:0000950


hgnc:12496

[PMID:33543479] [SUPPORT] Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. --- Explanation: Supports UBE3A as the primary disease gene.


HGNC.SYMBOL:15q11.2-q13 maternal deletion and imprinting-region abnormalities

[PMID:20301323] [SUPPORT] Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 80% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect --- Explanation: Supports the major non-sequence molecular mechanisms.


MONDO:0007113

[PMID:20301323] [SUPPORT] Individuals with AS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration associated with a very low recurrence risk. --- Explanation: Supports predominant de novo occurrence in clinical practice.

[PMID:20301323] [SUPPORT] Less commonly, an individual with AS has the disorder as the result of a genetic alteration associated with an imprinting pattern of autosomal dominant inheritance or variable recurrence risk. --- Explanation: Supports the imprinting-associated autosomal dominant inheritance mechanism.


MONDO:0005306

[PMID:33692806] [SUPPORT] New bone formation, determined by chronic inflammation involving the spine, leads to vertebral ankylosis, severe chronic pain and disability as major consequences of disease progression. --- Explanation: Evidence that chronic spinal inflammation causes pain as a major clinical manifestation of ankylosing spondylitis.


MONDO:0005306

[PMID:38371049] [SUPPORT] sacroiliitis on radiographs, in particular, are crucial for diagnosis. --- Explanation: Sacroiliitis is the hallmark articular manifestation of ankylosing spondylitis and is essential for diagnosis.


MONDO:0005306

[PMID:38371049] [SUPPORT] Clinical signs of AS include stiffness and inflammation in the back, eye inflammation, aortitis (inflammation of the aorta), and spinal ankylosis that impacts posture and fatigue. --- Explanation: Spinal stiffness is a cardinal clinical sign of ankylosing spondylitis, progressing to spinal ankylosis over time.


MONDO:0005306

[PMID:23999006] [SUPPORT] The pooled prevalence of uveitis was 25.8% --- Explanation: Uveitis is the most common extra-articular manifestation of ankylosing spondylitis, affecting approximately a quarter of patients.


MONDO:0005306

[PMID:33692806] [INDIRECT EVIDENCE] [SUPPORT] The unfolded protein response (UPR) theory postulates that unconventional HLA-B27 variants homodimerize instead of heterodimerize; the misfolded proteins accumulate in the intracellular compartment triggering endoplasmic reticulum stress and increasing IL-23 production. --- Explanation: Evidence supporting HLA-B27 misfolding mechanism that triggers ER stress and activates IL-23 production in ankylosing spondylitis.


MONDO:0005306

[PMID:33692806] [INDIRECT EVIDENCE] [SUPPORT] Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. --- Explanation: Review evidence confirming the central role of IL-23/IL-17 axis in ankylosing spondylitis pathogenesis and other autoimmune diseases.

[PMID:33692806] [INDIRECT EVIDENCE] [SUPPORT] The fundamental role played by the IL-23/IL-17 axis comes from several lines of evidence depicting a clear increase in IL-23 and IL-17 levels in the sera of AS patients (113). This observation is coupled with the increased number of Th17 cells in peripheral blood from AS patients (114). --- Explanation: Direct evidence of elevated IL-23 and IL-17 levels and increased Th17 cells in ankylosing spondylitis patients.


MONDO:0005306


MONDO:0005306

[PMID:33692806] [INDIRECT EVIDENCE] [PARTIAL] New bone formation, determined by chronic inflammation involving the spine, leads to vertebral ankylosis, severe chronic pain and disability as major consequences of disease progression. --- Explanation: Evidence linking chronic spinal inflammation to pathological new bone formation and ankylosis in ankylosing spondylitis.


HGNC.SYMBOL:HLA-B27

[PMID:33692806] [SUPPORT] The strongest genetic association is with the allele human leukocyte antigen B27 (HLA-B27) of the Major Histocompatibility Complex-I (MHC-I) gene, located on chromosome 6 (98). --- Explanation: Evidence confirming HLA-B27 as the strongest genetic risk factor for ankylosing spondylitis.


HGNC.SYMBOL:ERAP1

[PMID:33692806] [SUPPORT] In particular, single nucleotide polymorphisms (SNPs) in genes coding for aminopeptidases expressed in the endoplasmic reticulum (ER), such as ERAP1 and ERAP2, were identified in the past decade. These proteins trim peptides in the ER so that these molecules get to the right length, usually between 8 and 10 amino acids, to be presented by MHC-I molecules (107). --- Explanation: Evidence that ERAP1 genetic variants are associated with ankylosing spondylitis through effects on antigen processing and MHC-I presentation.


HGNC.SYMBOL:IL23R

[PMID:33692806] [SUPPORT] SNPs directly affecting the IL-23/IL-17 axis were described in AS and further stress the importance of this pathway. The most relevant are located in the genes coding for IL-23R and STAT3 and TYK2, which are downstream targets of IL-23 signaling (110, 111). --- Explanation: Evidence that IL23R variants are associated with ankylosing spondylitis, highlighting the importance of the IL-23/IL-17 pathway.


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:SMAD3


HGNC.SYMBOL:PRDM1


HGNC.SYMBOL:PTPN22


MONDO:8000010

[PMID:36575066] [SUPPORT] Venous thromboembolism belongs to the most frequent clinical manifestation of this syndrome. --- Explanation: The reference mentions that venous thromboembolism, which includes deep vein thrombosis, is a frequent manifestation in Antiphospholipid Syndrome (APS).

[PMID:10961585] [PARTIAL] In its classic presentation, the antiphospholipid syndrome manifests a combination of venous or arterial thrombosis... The manifestations often include a moderate thrombocytopenia and, less commonly, hemolysis. --- Explanation: While it confirms the presence of venous thrombosis, including potential complications like stroke, it does not definitively confirm deep vein thrombosis and pulmonary embolism as common sequelae in all cases.

[PMID:12627666] [SUPPORT] The relative frequency of ACLAs in association with arterial and venous thrombosis strongly suggests that they should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed. --- Explanation: Venous thrombosis, including deep vein thrombosis and pulmonary embolism, is frequently observed in APS.


MONDO:8000010

[PMID:26815583] [SUPPORT] Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction --- Explanation: The reference lists premature birth (preterm birth) as a form of obstetric morbidity associated with APS, supporting its categorization as a pregnancy-related phenotype.

[PMID:36756665] [SUPPORT] The pregnancy outcomes were not significantly different between NC-OAPS and OAPS groups. --- Explanation: The evidence suggests that patients with APS (OAPS) can experience similar pregnancy outcomes to those without the specific criteria of classical APS, which includes preterm birth.

[PMID:34280554] [SUPPORT] Patients with lupus anticoagulant positivity had an increased risk of preeclampsia (OR 2.10, p = 0.02, I2 = 48%), SGA (OR 1.78, p < 0.01, I2 = 0%) and preterm birth (OR 3.56, p = 0.01, I2 = 48%) --- Explanation: The meta-analysis found that APS patients, especially those with lupus anticoagulant positivity, have an increased risk of preterm birth, supporting the statement that APS phenotypes include pregnancy-related complications such as preterm birth.


MONDO:8000010

[PMID:8952756] [SUPPORT] a variable degree of thrombocytopenia occurs in approximately 20-40% of the patients with APS --- Explanation: Thrombocytopenia is a hematologic phenotype observed in APS patients.

[PMID:21303834] [SUPPORT] This article summarizes the studies analyzed on thrombocytopenia and skin manifestations --- Explanation: Thrombocytopenia is mentioned as a manifestation studied in APS.

[PMID:29316193] [SUPPORT] Thrombocytopenia is the most common non-criteria hematological feature in patients with antiphospholipid syndrome (APS). --- Explanation: Thrombocytopenia is a significant hematologic feature observed in APS.


MONDO:8000010

[PMID:26815583] [PARTIAL] Obstetric morbidity includes recurrent first trimester loss, stillbirth, intrauterine death, preeclam-psia, premature birth and fetal growth restriction --- Explanation: The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.

[PMID:32413497] [PARTIAL] Its major presentations are thrombotic (arterial, venous, or microvascular) and pregnancy morbidity (miscarriages, late intrauterine fetal demise, and severe pre-eclampsia). --- Explanation: The literature supports the association of antiphospholipid syndrome with preeclampsia, but it does not specify that the frequency is 'occasional'.


MONDO:8000010

[PMID:35536236] [SUPPORT] Thrombocytopenia, a frequent clinical manifestation in patients with APS, could be an independent predictor of recurrent thrombotic, obstetric and severe extracriteria events. --- Explanation: The study indicates thrombocytopenia is a frequent clinical manifestation in patients with primary APS.

[PMID:17426356] [SUPPORT] Other features include recurrent miscarriage, thrombocytopenia, and livedo reticularis. --- Explanation: Thrombocytopenia is mentioned as a clinical feature of APS, supporting its frequent occurrence.

[PMID:18417261] [SUPPORT] Thrombocytopenia is frequently found in APS patients, its incidence has ranged from 22-42% in different series. --- Explanation: The incidence range of 22-42% indicates that thrombocytopenia is a frequent hematologic manifestation in APS patients.


MONDO:8000010

[PMID:26223086] [SUPPORT] Livedo reticularis is a common cutaneous manifestation of APS and may be a prognostic marker of more severe disease. --- Explanation: This reference states that livedo reticularis is a common cutaneous manifestation of APS, supporting its categorization as a dermatologic manifestation.

[PMID:9204065] [SUPPORT] Cutaneous manifestations may occur as the first sign of antiphospholipid syndrome. These include livedo reticularis... --- Explanation: This reference confirms that livedo reticularis is one of the cutaneous manifestations of APS.

[PMID:35697016] [SUPPORT] This cross-sectional analysis of a large cohort of Serbian PAPS patients confirmed a strong relationship between livedo reticularis and arterial thrombosis... --- Explanation: This reference supports the association of livedo reticularis with APS, indicating its presence in patients with the syndrome.

[PMID:36112747] [SUPPORT] Livedo is a well-known skin condition in patients with systemic lupus erythematosus (SLE) which correspond to small vessels involvement. --- Explanation: This reference discusses the prevalence of livedo in patients with SLE and APS, supporting its categorization as a dermatologic manifestation.


MONDO:8000010

[PMID:17165009] [SUPPORT] A common cause of the huge variety of clinical manifestations is vaso-occlusive disease and not vasculitis in venous or arterial blood vessels of different sizes and sites (i.e. deep vein thrombosis, pulmonary embolism, cerebrovascular disease). --- Explanation: This review explicitly lists pulmonary embolism among the vaso-occlusive manifestations of APS.

[PMID:23073594] [SUPPORT] Deep vein thrombosis of lower extremity (37.7%) and cerebral infarction (24.59%) were the most common thrombosis events, and then pulmonary embolism, thrombotic microangiopathy and renal artery thrombosis were also common in APS patients. --- Explanation: This cohort study identifies pulmonary embolism as a common thrombotic manifestation in APS patients.


MONDO:8000010

[PMID:24741580] [SUPPORT] Typically, neurological manifestations of APS include thrombosis of cerebral vessels leading to stroke and requiring prompt initiation of treatment with antiplatelet drugs or anticoagulant therapy. --- Explanation: This review directly supports stroke as a common neurologic thrombotic manifestation of APS.

[PMID:23073594] [SUPPORT] Deep vein thrombosis of lower extremity (37.7%) and cerebral infarction (24.59%) were the most common thrombosis events, and then pulmonary embolism, thrombotic microangiopathy and renal artery thrombosis were also common in APS patients. --- Explanation: This cohort study identifies cerebral infarction as one of the most common thrombotic events in APS.


MONDO:8000010

[PMID:29867951] [INDIRECT EVIDENCE] [SUPPORT] The primary anti-phospholipid syndrome (APS) is characterized by the production of antibodies that bind the phospholipid-binding protein β2 glycoprotein I (β2GPI) or that directly recognize negatively charged membrane phospholipids in a manner that may contribute to arterial or venous thrombosis. --- Explanation: This review defines the initiating APS event as production of antibodies targeting beta2 glycoprotein I or phospholipids.

[PMID:33722752] [INDIRECT EVIDENCE] [SUPPORT] It is now widely accepted that antiphospholipid antibodies (aPL) have direct pathogenic effects and that B cells, notably through aPL production, play a key role in the development of antiphospholipid syndrome (APS). --- Explanation: This supports the role of adaptive immune cells, especially B cells, in generating pathogenic antiphospholipid antibodies.


MONDO:8000010


MONDO:8000010

[PMID:20822807] [INDIRECT EVIDENCE] [SUPPORT] Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. --- Explanation: This review supports endothelial activation as a central APS mechanism.


MONDO:8000010

[PMID:20822807] [INDIRECT EVIDENCE] [SUPPORT] Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. --- Explanation: This review supports monocyte activation with tissue factor overproduction as a core APS mechanism.


MONDO:8000010

[PMID:20822807] [INDIRECT EVIDENCE] [SUPPORT] Antiphospholipid antibodies promote activation of endothelial cells, monocytes, and platelets; and overproduction of tissue factor and thromboxane A2. --- Explanation: This review supports platelet activation as a discrete prothrombotic mechanism in APS.

[PMID:33878780] [INDIRECT EVIDENCE] [SUPPORT] aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. --- Explanation: This confirms platelet activation as part of a broader APS prothrombotic program.


MONDO:8000010

[PMID:20822807] [INDIRECT EVIDENCE] [SUPPORT] Complement activation might have a central pathogenetic role. --- Explanation: This review identifies complement as a core amplifier of APS pathogenesis.


MONDO:8000010

[PMID:33878780] [INDIRECT EVIDENCE] [SUPPORT] Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. --- Explanation: This establishes impaired fibrinolysis as a discrete APS mechanism rather than part of a bundled prothrombotic state.


MONDO:8000010

[PMID:19665761] [INDIRECT EVIDENCE] [SUPPORT] Recent clinical and experimental observations suggest that the pathophysiology of pregnancy failure in patients with APS may involve inflammation at the maternal-fetal interface and disruption of normal trophoblast function and survival, rather than a pro-thrombotic event. --- Explanation: This supports placental inflammation and trophoblast dysfunction as a distinct APS mechanism.

[PMID:19557318] [INDIRECT EVIDENCE] [SUPPORT] It provides a non-invasive method for the study of uteroplacental blood flow, being able to detect a condition of impaired placental perfusion, due to the presence of circulating antiphospholipid antibodies (aPL). --- Explanation: This supports impaired placental perfusion as part of the obstetric APS pathway.


MONDO:8000010

[PMID:22247356] [INDIRECT EVIDENCE] [SUPPORT] After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died... Neurologic damage is the most common cause of morbidity. --- Explanation: This cohort demonstrates cumulative damage accrual in APS over time.

[PMID:27198137] [INDIRECT EVIDENCE] [SUPPORT] The kidney is a major target organ in both primary and secondary antiphospholipid syndrome... APSN is a vascular nephropathy characterized by small vessel vaso-occlusive lesions. --- Explanation: This supports kidney injury as a representative organ-damage consequence of APS vaso-occlusion.

[PMID:36575066] [INDIRECT EVIDENCE] [SUPPORT] Venous thromboembolism belongs to the most frequent clinical manifestation of this syndrome... we summarised basic pathophysiological mechanisms of venous thrombosis and lung embolism development. --- Explanation: This supports pulmonary injury through thromboembolic complications in APS.

[PMID:38368768] [INDIRECT EVIDENCE] [SUPPORT] APS patients had a higher frequency of damage accrual. Microangiopathy and non-criteria manifestations were independent risk factors for damage accrual. --- Explanation: This confirms that recurrent vascular injury in APS produces long-term damage accrual.


MONDO:8000010

[PMID:26753212] [INDIRECT EVIDENCE] [SUPPORT] Catastrophic antiphospholipid syndrome is the most dangerous form of the antiphospholipid syndrome, which is characterized by rapid onset of thrombosis in small vessels of many organs and intravascular coagulation, thrombocytopenia and hemolytic anemia. --- Explanation: This defines CAPS as widespread small-vessel thrombosis with hematologic complications.

[PMID:26753212] [INDIRECT EVIDENCE] [SUPPORT] The syndrome develops over a short period of time with acute multi-organ failure, including kidney, respiratory, cardiovascular, central nervous system and adrenal glands, often associated with disseminated thrombotic microangiopathy. --- Explanation: This supports acute multiorgan failure from disseminated microvascular thrombosis as the most severe APS mechanistic outcome.


MAXO:0000058

[PMID:18303659] [SUPPORT] Oral anticoagulants are the best available and most effective treatment for the secondary prevention of recurrent venous or arterial thrombosis. Patients with APS are treated with long-term therapy to prolong the INR to 2.0-3.0. --- Explanation: This review supports long-term warfarin-based oral anticoagulation as standard secondary prevention for thrombotic APS.

[PMID:20822807] [SUPPORT] Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. --- Explanation: This review confirms long-term oral anticoagulation as the basis of treatment for thrombotic APS.


CHEBI:10033

[PMID:18303659] [INDIRECT EVIDENCE] [SUPPORT] Oral anticoagulants are the best available and most effective treatment for the secondary prevention of recurrent venous or arterial thrombosis. Patients with APS are treated with long-term therapy to prolong the INR to 2.0-3.0. --- Explanation: This review supports long-term warfarin-based oral anticoagulation as standard secondary prevention for thrombotic APS.

[PMID:20822807] [INDIRECT EVIDENCE] [SUPPORT] Therapy of thrombosis is based on long-term oral anticoagulation and patients with arterial events should be treated aggressively. --- Explanation: This review confirms long-term oral anticoagulation as the basis of treatment for thrombotic APS.


MAXO:0000058

[PMID:18303659] [SUPPORT] Low-molecular-weight heparin in combination with low-aspirin dose is a reasonable strategy to avoid pregnancy loss in women with this syndrome. --- Explanation: This supports combined heparin and aspirin therapy as standard management for obstetric APS.

[PMID:22341691] [SUPPORT] Heparin and low-dose aspirin are the main treatments. --- Explanation: This pregnancy-focused review identifies heparin plus low-dose aspirin as the main treatment approach for obstetric APS.


CHEBI:28304

[PMID:18303659] [INDIRECT EVIDENCE] [SUPPORT] Low-molecular-weight heparin in combination with low-aspirin dose is a reasonable strategy to avoid pregnancy loss in women with this syndrome. --- Explanation: This supports combined heparin and aspirin therapy as standard management for obstetric APS.

[PMID:22341691] [INDIRECT EVIDENCE] [SUPPORT] Heparin and low-dose aspirin are the main treatments. --- Explanation: This pregnancy-focused review identifies heparin plus low-dose aspirin as the main treatment approach for obstetric APS.


CHEBI:15365


MAXO:0000058

[PMID:20822807] [PARTIAL] Hydroxychloroquine is a potential additional treatment for this syndrome. --- Explanation: This review supports hydroxychloroquine as an adjunct rather than a standalone standard therapy in APS.

[PMID:26125104] [PARTIAL] The addition to standard treatment of pleiotropic agents such as hydroxychloroquine, statins and vitamin D could allow better disease control. --- Explanation: This review supports hydroxychloroquine as an add-on strategy that may improve disease control in APS.


CHEBI:5801

[PMID:20822807] [INDIRECT EVIDENCE] [PARTIAL] Hydroxychloroquine is a potential additional treatment for this syndrome. --- Explanation: This review supports hydroxychloroquine as an adjunct rather than a standalone standard therapy in APS.

[PMID:26125104] [INDIRECT EVIDENCE] [PARTIAL] The addition to standard treatment of pleiotropic agents such as hydroxychloroquine, statins and vitamin D could allow better disease control. --- Explanation: This review supports hydroxychloroquine as an add-on strategy that may improve disease control in APS.


HGNC.SYMBOL:HLA-DR7

[PMID:8792513] [SUPPORT] This familial tendency could be genetically determined, because APS, aCL, and LAC occur in families carrying haplotypes which contain HLA-DR4, -DR7, and -DRw53. --- Explanation: This review directly supports HLA-DR7 as a reported susceptibility-associated haplotype in APS families.

[PMID:8792513] [SUPPORT] Population studies on primary APS also indicate that HLA genes have a role in conferring susceptibility to develop primary APS. Again, DR4, DR7, and DRw53 are the relevant loci. --- Explanation: This further supports HLA-DR7 as one of the repeatedly implicated HLA loci in primary APS susceptibility.


HGNC.SYMBOL:HLA-DR4

[PMID:8792513] [SUPPORT] This familial tendency could be genetically determined, because APS, aCL, and LAC occur in families carrying haplotypes which contain HLA-DR4, -DR7, and -DRw53. --- Explanation: This supports HLA-DR4 as part of APS-associated family haplotypes.

[PMID:8792513] [SUPPORT] Population studies on primary APS also indicate that HLA genes have a role in conferring susceptibility to develop primary APS. Again, DR4, DR7, and DRw53 are the relevant loci. --- Explanation: This provides additional support that DR4 is among the HLA loci repeatedly implicated in primary APS susceptibility.


ECTO:6000029

[PMID:15658543] [PARTIAL] The proportion of smokers was higher in APS patients, though smoking did not provoke thrombotic complications. --- Explanation: Smoking was more common in APS cohorts, supporting it as a relevant exposure, although this study did not show smoking independently provoked thrombosis.


ECTO:3000000

[PMID:17531174] [PARTIAL] An association between infections and antiphospholipid antibodies (aPL) has been reported in several epidemiologic and experimental studies. Infection-induced aPL have been traditionally regarded as transient and were generally not associated with clinical features of antiphospholipid syndrome. --- Explanation: The statement is partially supported because while there is an association between infections and antiphospholipid antibodies, infection-induced aPL are traditionally regarded as transient and not generally associated with the clinical features of antiphospholipid syndrome.

[PMID:22617823] [SUPPORT] PURPOSE OF REVIEW: To present scientific evidence supporting the infectious origin for the antiphospholipid syndrome (APS) by molecular mimicry between pathogens, infection and vaccination with β2-glycoprotein I (β2-GPI) molecule. --- Explanation: This review supports infection exposure as a plausible upstream trigger for APS-related autoimmunity through molecular mimicry.


MONDO:0013902

[PMID:22275001] [SUPPORT] Both patients carrying functionally significant SMAD6 variants had bicuspid aortic valves, the commonest cardiovascular malformation, --- Explanation: This provides direct phenotype-level support for bicuspid aortic valve as the defining lesion.


hgnc:6772

[PMID:28659821] [SUPPORT] SMAD6 was identified as the most important known gene in the etiology of BAV with associated TAA. --- Explanation: This large cohort establishes SMAD6 as the principal known gene for the bicuspid valve-thoracic aneurysm phenotype captured here.

[PMID:22275001] [SUPPORT] We conclude that low-frequency deleterious variants in SMAD6 predispose to CVM. --- Explanation: This original report establishes SMAD6 as a causal contributor to the cardiovascular malformation branch.


MONDO:0013902

[PMID:28659821] [SUPPORT] Transmission of BAV/TAA mostly complies with an autosomal dominant inheritance pattern, displaying reduced penetrance and variable expressivity --- Explanation: This cohort review explicitly supports autosomal dominant inheritance with incomplete penetrance and variable expressivity in the SMAD6-associated bicuspid valve-aortopathy phenotype.


MONDO:0007041

[PMID:7719344] [SUPPORT] Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. --- Explanation: Craniosynostosis is established as a defining clinical feature of Apert syndrome.


MONDO:0007041

[PMID:26330906] [SUPPORT] Apert syndrome is a rare congenital disorder characterized by craniosynostosis, midface hypoplasia and symmetric syndactyly of hands and feet. --- Explanation: This review directly supports midface hypoplasia as a core craniofacial feature of Apert syndrome.


MONDO:0007041

[PMID:25206244] [SUPPORT] Craniofacial deformities include cone-shaped calvarium, fat forehead, prop-tosis, hypertelorism and short nose with a bulbous tip. --- Explanation: This case-based review directly lists proptosis among the characteristic craniofacial findings of Apert syndrome.


MONDO:0007041

[PMID:7719344] [SUPPORT] Apert syndrome is a distinctive human malformation comprising craniosynostosis and severe syndactyly of the hands and feet. --- Explanation: Defines syndactyly of hands and feet as a core diagnostic feature of Apert syndrome.


MONDO:0007041

[PMID:26330906] [SUPPORT] Apert syndrome is a rare congenital disorder characterized by craniosynostosis, midface hypoplasia and symmetric syndactyly of hands and feet. --- Explanation: This review directly supports syndactyly of the feet as a defining phenotype of Apert syndrome.


MONDO:0007041

[PMID:2065494] [SUPPORT] The characteristic "hitchhiker" posture or radial clinodactyly of these short but broad digits is caused by an abnormal proximal phalanx. --- Explanation: This Apert thumb anatomy paper directly supports short, broad, radially deviated thumbs as a characteristic hand feature.


MONDO:0007041

[PMID:3351902] [SUPPORT] Fourteen patients (48%) had a normal or borderline IQ (greater than 70), nine patients (31%) were mildly mentally retarded (IQ 50 to 70), four patients (14%) were moderately retarded (IQ 35 to 49), and two patients (7%) were severely retarded (IQ less than 35). --- Explanation: This long-term follow-up study supports variable cognitive outcome, including frequent intellectual disability, in Apert syndrome.


MONDO:0007041

[PMID:15389579] [INDIRECT EVIDENCE] [SUPPORT] FGF2 secretion was greater. --- Explanation: Apert P253R osteoblasts show increased FGF2 output, supporting a reinforcing autocrine signaling loop.

[PMID:15389579] [INDIRECT EVIDENCE] [SUPPORT] All together these findings suggest increased constitutive receptor activity in Apert mutant osteoblasts and an autocrine loop involving the FGF2 pathway in modulation of Apert osteoblast behavior. --- Explanation: This directly supports a constitutively active FGFR2/FGF2 autocrine signaling node.


MONDO:0007041


MONDO:0007041

[PMID:19117954] [INDIRECT EVIDENCE] [SUPPORT] WT and MT FGFR2 induced ERK1/2 but not JNK or PI3K/AKT phosphorylation. --- Explanation: This shows that activated FGFR2 engages the ERK1/2 cascade in the Apert model.


MONDO:0007041

[PMID:19117954] [INDIRECT EVIDENCE] [SUPPORT] MT, but not WT, also increased protein kinase C (PKC) activity. --- Explanation: This shows mutant-specific activation of the PKCalpha signaling branch.


MONDO:0007041

[PMID:19117954] [INDIRECT EVIDENCE] [SUPPORT] Both WT and MT FGFR2 increased early and late osteoblast gene expression and matrix mineralization. --- Explanation: This directly supports enhanced osteogenic differentiation and mineralization in the Apert FGFR2 model.


MONDO:0007041

[PMID:24259495] [INDIRECT EVIDENCE] [SUPPORT] In Ap mice, the coronal suture (CS) was fused prematurely at P1. --- Explanation: The Apert mouse model directly supports premature coronal suture fusion as a tissue-level mechanistic event.


MONDO:0007041

[PMID:26330906] [INDIRECT EVIDENCE] [SUPPORT] Abnormalities associated with Apert syndrome include premature fusion of coronal sutures system (coronal sutures and less frequently lambdoid suture) resulting in brachiturricephalic dismorphism and impaired skull base growth. --- Explanation: This supports impaired skull-base growth as a distinct downstream consequence of Apert craniosynostosis.


MAXO:0001291

[PMID:31895846] [SUPPORT] The purpose of this study is to review 10 years of surgical experience in the management of Apert syndrome, focusing on an updated algorithm which includes hand reconstruction and posterior vault distraction osteogenesis (PVDO). --- Explanation: This Apert-specific surgical series directly supports cranial vault expansion as part of standard operative management.

[PMID:34051898] [SUPPORT] Posterior cranial vault distraction osteogenesis is a powerful, reliable, low-morbidity method to achieve intracranial expansion. --- Explanation: This cranial vault remodeling review directly supports its use to expand cranial volume in syndromic craniosynostosis.


MAXO:0000004

[PMID:2732824] [SUPPORT] Midface advancement by Le Fort III osteotomy is a common procedure in craniofacial surgery. --- Explanation: This study directly supports Le Fort III osteotomy as an established midface advancement procedure in patients with Apert syndrome.

[PMID:23358017] [SUPPORT] Bipartition distraction is an effective procedure with which to differentially advance the central face in Apert syndrome. It improves both function and aesthetics. --- Explanation: This Apert series supports monobloc/frontofacial advancement approaches for functional and aesthetic improvement.


MAXO:0000004

[PMID:1648464] [SUPPORT] Surgical correction of syndactyly of the Apert hand should begin by 6 months and be completed by 3 years of age. --- Explanation: This hand surgery review directly supports staged early syndactyly release in Apert syndrome.

[PMID:29994846] [SUPPORT] Apert hand reconstruction requires complex surgical planning. --- Explanation: This modern reconstructive series supports syndactyly release as a complex, multistage surgical treatment for Apert hands.


hgnc:3689

[PMID:7719344] [PARTIAL] We have identified specific missense substitutions involving adjacent amino acids (Ser252Trp and Pro253Arg) in the linker between the second and third extracellular immunoglobulin (Ig) domains of fibroblast growth factor receptor 2 (FGFR2) in all 40 unrelated cases of Apert syndrome studied. --- Explanation: Landmark study identifying S252W and P253R as the causative mutations in 100% of 40 unrelated Apert syndrome cases examined.


MONDO:0007041

[PMID:2061407] [SUPPORT] The familial cases, the equal number of affected males and females, and the increased paternal age in sporadic cases strongly suggest autosomal dominant inheritance. --- Explanation: This family study directly supports autosomal dominant inheritance in Apert syndrome.


MONDO:0008814

[PMID:26467175] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Identifies spastic paraparesis as a hallmark feature of ARG1 deficiency.

[PMID:22633632] [SUPPORT] Progressive spastic diplegia constituted the key clinical abnormality in this group, but variability in clinical presentation and progression were evident in our series. --- Explanation: Confirms progressive spastic diplegia as the key clinical abnormality in a 16-patient cohort.


MONDO:0008814

[PMID:26467175] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Describes hyperammonemia as infrequent but present during catabolic stress.

[PMID:38292042] [SUPPORT] Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. --- Explanation: Confirms that metabolite accumulation is part of the ARG1-D clinical spectrum.


MONDO:0008814

[PMID:22633632] [SUPPORT] Seizures in hyperargininemia may be more common than reported in previous studies. --- Explanation: Directly supports that seizures are frequent and potentially underreported.

[PMID:22633632] [SUPPORT] Hyperargininemia is an autosomal recessive metabolic disorder caused by a deficiency of enzyme arginase I. It is a rare pan-ethnic disease with a clinical presentation distinct from that of other urea cycle disorders, and hyperammonemic encephalopathy is not usually observed. --- Explanation: Confirms distinct clinical presentation where seizures, not hyperammonemic encephalopathy, dominate.


MONDO:0008814

[PMID:26467175] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Directly identifies progressive intellectual impairment as a clinical feature of ARG1 deficiency.


MONDO:0008814


MONDO:0008814

[PMID:26467175] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Identifies persistent growth retardation as a characteristic feature of ARG1 deficiency.


MONDO:0008814

[PMID:22633632] [SUPPORT] Hyperargininemia is one of the few treatable causes of pediatric spastic paraparesis, and can be confused with cerebral palsy. --- Explanation: Identifies spasticity as a dominant feature frequently confused with cerebral palsy.


MONDO:0008814

[PMID:22633632] [SUPPORT] Hyperargininemia is an autosomal recessive metabolic disorder caused by a deficiency of enzyme arginase I. It is a rare pan-ethnic disease with a clinical presentation distinct from that of other urea cycle disorders, and hyperammonemic encephalopathy is not usually observed. --- Explanation: Confirms that hyperammonemic encephalopathy can occur but is not a usual finding.


MONDO:0008814

[PMID:38292042] [SUPPORT] Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. --- Explanation: Confirms marked increases in plasma arginine as the defining biochemical characteristic.

[PMID:26467175] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Identifies hyperargininemia as the primary biochemical finding in ARG1 deficiency.


MONDO:0008814

[PMID:22633632] [SUPPORT] Features distinguishing hyperargininemia from cerebral palsy and hereditary spastic paraplegia are emphasized in this large series of patients. --- Explanation: Clinical and neuroimaging findings help distinguish hyperargininemia from other spastic disorders.


MONDO:0008814

[PMID:26467175] [INDIRECT EVIDENCE] [SUPPORT] ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. --- Explanation: Supports ARG1 deficiency as the initiating molecular defect in arginase deficiency.


MONDO:0008814

[PMID:38292042] [INDIRECT EVIDENCE] [SUPPORT] Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. --- Explanation: Confirms hyperargininemia as the central biochemical feature of ARG1-D.


MONDO:0008814

[PMID:26467175] [INDIRECT EVIDENCE] [PARTIAL] This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. --- Explanation: Reviews pathophysiology of ARG1 deficiency but the abstract does not specifically detail guanidino compound neurotoxic mechanisms.


MONDO:0008814

[PMID:39449289] [INDIRECT EVIDENCE] [PARTIAL] LNP-formulated mRNA therapy has been assayed preclinically for citrullinemia type I (CTLN1), adolescent and adult citrin deficiency, argininosuccinic aciduria, arginase deficiency and ornithine transcarbamylase deficiency, in the latter case has progressed to the clinical trials phase. --- Explanation: Confirms preclinical mRNA therapy testing for arginase deficiency but does not specifically address myelination outcomes.

[PMID:22633632] [INDIRECT EVIDENCE] [SUPPORT] Progressive spastic diplegia constituted the key clinical abnormality in this group, but variability in clinical presentation and progression were evident in our series. --- Explanation: Clinical evidence of progressive spasticity consistent with corticospinal tract and white matter pathology.


MONDO:0008814

[PMID:26467175] [INDIRECT EVIDENCE] [PARTIAL] Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. --- Explanation: Mentions non-urea cycle ARG1 activities but does not specifically detail NO pathway dysregulation in the abstract.


MAXO:0000088


MAXO:0000058


MAXO:0000058

[PMID:38292042] [SUPPORT] In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. --- Explanation: Demonstrates sustained clinical mobility improvements beyond biochemical correction.


MAXO:0001175


MAXO:0000950

[PMID:22633632] [SUPPORT] Hyperargininemia is one of the few treatable causes of pediatric spastic paraparesis, and can be confused with cerebral palsy. --- Explanation: Identifying the treatable nature of spasticity supports active spasticity management.


MAXO:0000058

[PMID:22633632] [SUPPORT] Seizures in hyperargininemia may be more common than reported in previous studies. --- Explanation: High seizure frequency supports the need for antiepileptic management.


MAXO:0000124

[PMID:28659245] [SUPPORT] Improved newborn screening effectiveness should lead to better case detection and more rapid treatment to lower plasma arginine levels hence improving long term outcome of individuals with hyperargininemia. --- Explanation: Supports early detection through newborn screening for improved outcomes.


MAXO:0000079

[PMID:26467175] [SUPPORT] Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. --- Explanation: Autosomal recessive inheritance pattern supports the role of genetic counseling.


HGNC.SYMBOL:ARG1 pathogenic variants

[PMID:26467175] [SUPPORT] This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. --- Explanation: Describes the genetic basis including mutation spectrum and functional consequences.


MONDO:0008815

[PMID:38198573] [SUPPORT] Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype --- Explanation: Directly supports hyperammonemia as a key presenting feature of ASA.

[PMID:30723942] [SUPPORT] The clinical presentation was initially described as similar to other urea cycle defects, but increasing evidence has shown overtime an atypical systemic phenotype with a paradoxical observation, that is, a higher rate of neurological complications contrasting with a lower rate of hyperammonaemic episodes. --- Explanation: Supports hyperammonemia but notes paradoxically lower rate compared to other UCDs.


MONDO:0008815

[PMID:30723942] [SUPPORT] The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels. --- Explanation: Supports encephalopathy risk and poor long-term neurological outcomes despite treatment.


MONDO:0008815

[PMID:38044746] [SUPPORT] Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. --- Explanation: Supports neurocognitive deficits as a key feature of ASA with NO-mediated mechanism.


MONDO:0008815

[PMID:38044746] [SUPPORT] Patients present with developmental delay, epilepsy and movement disorder --- Explanation: Directly lists epilepsy as a presenting feature of ASA.


MONDO:0008815

[PMID:38044746] [SUPPORT] Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. --- Explanation: Provides cohort data on movement disorder incidence and temporal characteristics.


MONDO:0008815

[PMID:38044746] [SUPPORT] Patients present with developmental delay, epilepsy and movement disorder --- Explanation: Directly lists developmental delay as a presenting feature of ASA.


MONDO:0008815

[PMID:31990680] [PARTIAL] Liver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. --- Explanation: Provides human clinical context that hepatomegaly is a recognized liver manifestation across UCDs, including ASLD.

[PMID:31990680] [SUPPORT] The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen --- Explanation: Supports hepatomegaly as a feature of ASLD in both human and mouse model.


MONDO:0008815

[PMID:31990680] [SUPPORT] We demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. --- Explanation: Quantifies prevalence and clinical correlates of chronic transaminase elevation.


MONDO:0008815

[PMID:31990680] [SUPPORT] ultrasound with shear wave elastography and FibroTest revealed increased echogenicity and liver stiffness, even in individuals with ASLD and normal aminotransferases --- Explanation: Demonstrates subclinical liver fibrosis detectable beyond standard ALT/AST monitoring.


MONDO:0008815

[PMID:30075114] [SUPPORT] we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension --- Explanation: Establishes ASLD as a Mendelian cause of endothelial-dependent hypertension.