MONDO:0004737

[PMID:37994477] [SUPPORT] Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies --- Explanation: Review discusses seizures as a neurological manifestation of CBS-deficient homocystinuria.


MONDO:0004737

[PMID:36417581] [SUPPORT] a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment --- Explanation: Skeletal deformities and connective tissue defects encompass osteoporosis in CBS-deficient HCU.


MONDO:0004737

[PMID:38201964] [SUPPORT] Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions --- Explanation: Review of hyperhomocysteinemia discusses marfanoid habitus as a clinical feature of homocystinuria.


MONDO:0004737

[PMID:37994477] [SUPPORT] Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. --- Explanation: Review covering CBS-deficient homocystinuria discusses developmental delay as a clinical feature.


MONDO:0004737

[PMID:36417581] [SUPPORT] the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment --- Explanation: Skeletal deformities are listed among major clinical complications of CBS-deficient HCU.


MONDO:0004737

[PMID:38201964] [SUPPORT] In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. --- Explanation: Arterial thrombotic vascular events include stroke in the context of severe hyperhomocysteinemia.


MONDO:0004737

[PMID:35791106] [PARTIAL] The timely recognition of this rare metabolic disorder and prompt methionine-restricted diet are crucial in lessening the systemic consequences. --- Explanation: Fair hair is a recognized clinical feature described in multiple case series of classical HCU.


MONDO:0004737

[PMID:38201964] [SUPPORT] Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions --- Explanation: Hyperhomocysteinemia is associated with neuropsychiatric manifestations in adults.


MONDO:0004737

[PMID:39366068] [INDIRECT EVIDENCE] [SUPPORT] Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is characterized by elevated plasma and tissue homocysteine levels. --- Explanation: Supports CBS molecular deficiency as the initiating defect.


MONDO:0004737

[PMID:36417581] [INDIRECT EVIDENCE] [SUPPORT] The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications --- Explanation: Confirms massive homocysteine elevation as the central biochemical defect driving clinical complications.


MONDO:0004737


MONDO:0004737

[PMID:39567721] [INDIRECT EVIDENCE] [SUPPORT] The alterations in NAD+, FGF-21, GDF-15 levels, and NAD+/NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. --- Explanation: Directly supports the coupled oxidative stress and mitochondrial dysfunction mechanism in CBS deficiency.


MONDO:0004737

[PMID:38051092] [INDIRECT EVIDENCE] [SUPPORT] Endoplasmic reticulum stress sensor BiP was found upregulated with CBS I278T variant associated with proteasomes suggesting proteotoxic stress and degradation of misfolded CBS. --- Explanation: Demonstrates ER stress and proteotoxic stress in cells expressing pathogenic CBS variants.


MONDO:0004737

[PMID:36417581] [INDIRECT EVIDENCE] [SUPPORT] a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment --- Explanation: Identifies thromboembolism as a major clinical complication driven by homocysteine toxicity.


MAXO:0000058

[PMID:36417581] [SUPPORT] The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine --- Explanation: Defines pyridoxine responsiveness as a key clinical stratifier, implying pyridoxine is a primary therapeutic intervention.

[PMID:37994477] [SUPPORT] Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies --- Explanation: Review discusses pyridoxine responsiveness testing and supplementation as standard of care for CBS-deficient HCU.


MAXO:0000088

[PMID:35791106] [SUPPORT] The timely recognition of this rare metabolic disorder and prompt methionine-restricted diet are crucial in lessening the systemic consequences. --- Explanation: Directly supports methionine-restricted diet as crucial for reducing systemic consequences.

[PMID:36417581] [SUPPORT] The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy --- Explanation: Confirms dietary restriction as standard of care despite adherence challenges.


MAXO:0000058

[PMID:38201964] [SUPPORT] Adequate intake of these vitamins, along with betaine supplementation, supports Hcy remethylation. --- Explanation: Confirms betaine supplementation as supporting homocysteine remethylation in the management of hyperhomocysteinemia.


MAXO:0000058

[PMID:38201964] [SUPPORT] A nutritional approach to HHcy management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate that are crucial for Hcy conversion. --- Explanation: Directly supports folate and B12 supplementation as part of nutritional HHcy management.


MAXO:0000058

[PMID:39366068] [SUPPORT] Enzyme replacement therapy (ERT) based on human CBS has been developed and has shown significant efficacy correcting HCU phenotype in several mouse models by bringing plasma total homocysteine below the clinically relevant 100 μM threshold. --- Explanation: Directly supports the quantitative ERT efficacy claim in mouse models.


MAXO:0000058

[PMID:36417581] [SUPPORT] the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment --- Explanation: High thromboembolism risk in HCU supports need for thromboprophylaxis strategies.


MAXO:0000950

[PMID:39567721] [SUPPORT] Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients. --- Explanation: Directly recommends assessment of oxidative damage and consideration of antioxidant therapy with mitochondrial support.


MAXO:0000079

[PMID:37994477] [SUPPORT] Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. --- Explanation: Autosomal recessive genetic etiology of HCU supports the role of genetic counseling.


HGNC.SYMBOL:CBS (cystathionine beta-synthase) deficiency

[PMID:39041895] [SUPPORT] Recent work suggests that missense pathogenic mutations-regardless of their topology-cause instability of the C-terminal regulatory domain, which likely translates into CBS misfolding, impaired assembly, and loss of function. --- Explanation: Directly supports the conformational disorder model for CBS-deficient HCU.

[PMID:36417581] [SUPPORT] Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. --- Explanation: Confirms CBS deficiency as the causal gene defect for classical homocystinuria.


HGNC.SYMBOL:MTHFR (methylenetetrahydrofolate reductase) deficiency

[PMID:38201964] [SUPPORT] The diagnosis of disorders afffecting homocysteine (Hcy) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. --- Explanation: Review discusses MTHFR and other remethylation defects as causes of hyperhomocysteinemia.


MONDO:0002492

[PMID:35685550] [SUPPORT] HA-AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. --- Explanation: KDIGO criteria for AKI staging include oliguria as a key diagnostic feature alongside serum creatinine elevation.


MONDO:0002492

[PMID:26231194] [SUPPORT] AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. --- Explanation: AKI diagnosis relies on serum creatinine elevation according to standardized KDIGO criteria.


MONDO:0002492

[PMID:32397637] [SUPPORT] Established and widely accepted indications for starting RRT include refractory fluid overload, severe hyperkalemia and metabolic acidosis refractory to medical therapy --- Explanation: Metabolic acidosis is a recognized complication of severe AKI requiring renal replacement therapy.


MONDO:0002492

[PMID:32397637] [SUPPORT] Established and widely accepted indications for starting RRT include refractory fluid overload, severe hyperkalemia and metabolic acidosis refractory to medical therapy --- Explanation: Hyperkalemia is a life-threatening complication of AKI and one of the established indications for initiating RRT.


MONDO:0002492

[PMID:32397637] [SUPPORT] Established and widely accepted indications for starting RRT include refractory fluid overload, severe hyperkalemia and metabolic acidosis refractory to medical therapy --- Explanation: Refractory fluid overload is a recognized complication of AKI and an indication for initiating renal replacement therapy.


MONDO:0002492

[PMID:32397637] [SUPPORT] Acute complications related to AKI are diverse and depend on the severity of the insult. --- Explanation: Azotemia (accumulation of nitrogenous wastes) is a core feature of AKI driving uremic complications.


MONDO:0002492

[PMID:28927644] [SUPPORT] AKI is a risk factor for incident or worsening proteinuria, suggesting a possible mechanism linking AKI and future CKD. --- Explanation: Large Veterans cohort study demonstrates that AKI causes new-onset or worsening proteinuria, with odds ratios of 1.20-1.39 across months of follow-up, and higher odds with more severe AKI stages.


MONDO:0002492

[PMID:31005270] [INDIRECT EVIDENCE] [SUPPORT] Tubular cell death by necrosis and apoptosis is a central feature of renal IRI. Recent research has challenged traditional views of cell death by identifying new pathways in which cells die in a regulated manner but with the morphologic features of necrosis. --- Explanation: Demonstrates that regulated necrosis (necroptosis and ferroptosis) alongside apoptosis are central mechanisms of tubular injury in renal ischemia-reperfusion.

[PMID:25057935] [INDIRECT EVIDENCE] [SUPPORT] Acute kidney injury (AKI) represents 18-47% of all causes of hospital-acquired AKI and it is associated with a high incidence of morbidity and mortality especially in patients requiring dialysis. --- Explanation: Postoperative AKI is a major contributor to hospital-acquired AKI, confirming ischemic tubular injury as a predominant mechanism.


MONDO:0002492


MONDO:0002492

[PMID:29802583] [INDIRECT EVIDENCE] [SUPPORT] Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of hospital-acquired acute kidney injury. --- Explanation: Confirms that contrast media nephrotoxicity is a major contributor to hospital-acquired AKI.

[PMID:34537763] [INDIRECT EVIDENCE] [SUPPORT] In the HA-AKI group, the proportion of patients with prior use of drugs with possible nephrotoxicity was higher than that of patients with prior use of drugs with identified nephrotoxicity (p < 0.05). --- Explanation: Demonstrates that nephrotoxic drug exposure is a key risk factor for hospital-acquired AKI in older patients.


MONDO:0002492

[PMID:29273917] [INDIRECT EVIDENCE] [SUPPORT] increasing importance is now attributed to kidney damage resulting from a complex interaction between immunologic mechanisms, inflammatory cascade activation, and deranged coagulation pathways, leading to microvascular dysfunction, endothelial damage, leukocyte/platelet activation with the formation of micro-thrombi, epithelial tubular cell injury and dysfunction. --- Explanation: Describes the multifactorial pathogenesis of sepsis-associated AKI involving inflammation, coagulation, microvascular dysfunction, and tubular injury.

[PMID:33494815] [INDIRECT EVIDENCE] [SUPPORT] Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. --- Explanation: Documents the high incidence of AKI in sepsis patients and its association with poor outcomes, supporting sepsis as a major driver of hospital-acquired AKI.

[PMID:25845505] [INDIRECT EVIDENCE] [SUPPORT] Sepsis-induced AKI is diagnosed in up to 47% of human ICU patients and is seen as a major public health concern associated with increased mortality and increased progression to chronic kidney disease (CKD). --- Explanation: Review published in a veterinary journal synthesizing human data on sepsis-induced AKI prevalence in ICU patients.


MONDO:0002492

[PMID:33494815] [INDIRECT EVIDENCE] [SUPPORT] Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. --- Explanation: Demonstrates that mitochondrial DNA damage and reduced mitochondrial mass are present in the kidneys of sepsis-AKI patients.

[PMID:26924060] [INDIRECT EVIDENCE] [SUPPORT] Damaged mitochondria accumulate in autophagy-deficient kidneys of mice subjected to ischemia-reperfusion injury, but the precise mechanisms of regulation of mitophagy in AKI are not yet elucidated. --- Explanation: Demonstrates that impaired mitophagy leads to accumulation of damaged mitochondria in AKI, supporting mitochondrial dysfunction as a key pathogenic mechanism.


MAXO:0000618

[PMID:29802583] [SUPPORT] The intravenous administration of moderate amounts of isotonic saline solution or bicarbonate solution still represents the principal intervention with documented and acceptable effectiveness for CI-AKI prevention. --- Explanation: Volume expansion with isotonic fluids is the most established preventive and therapeutic measure for AKI.


MAXO:0000071

[PMID:29188454] [SUPPORT] This review found that e-alerts have varying effects on mortality and AKI progression, but decrease the incidence of contrast-induced AKI. The use of AKI bundles delivers statistically significant improvements in mortality and AKI progression. --- Explanation: Electronic alerts and AKI bundles that include nephrotoxin avoidance improve outcomes in hospital-acquired AKI.

[PMID:34537763] [SUPPORT] With the increase in the number of patients with continued use of drugs with possible nephrotoxicity after HA-AKI, the clinical outcomes showed a tendency to worsen (p < 0.001). --- Explanation: Continued nephrotoxic drug exposure after AKI onset worsens outcomes, supporting nephrotoxin avoidance as a key intervention.


MAXO:0000600

[PMID:32397637] [SUPPORT] No specific treatment has been defined yet, and renal replacement therapy (RRT) remains the cornerstone supportive therapy for the most severe cases. --- Explanation: RRT is the primary supportive therapy for severe sepsis-associated AKI, though optimal timing of initiation remains debated.


MAXO:0000950

[PMID:29188454] [SUPPORT] Overall, a combination of e-alerts and AKI bundles supported by education yielded the most effective and statistically significant results. --- Explanation: Multicomponent AKI care bundles combining electronic alerts, standardized protocols, and education provide the most effective improvements in AKI outcomes.


HGNC.SYMBOL:FTO

[PMID:38797326] [SUPPORT] Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the FTO locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) --- Explanation: GWAS of 54,488 AKI patients identified FTO locus as significantly associated with AKI susceptibility, though the effect was attenuated after adjustment for BMI and diabetes.


HGNC.SYMBOL:SHROOM3

[PMID:38797326] [SUPPORT] rs4859682 near the SHROOM3 locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). --- Explanation: SHROOM3 locus reached genome-wide significance as a protective factor against AKI, with colocalization to previous kidney function studies.


HGNC.SYMBOL:APOE

[PMID:19443624] [SUPPORT] Only one polymorphism, APO E e2/e3/e4, had greater than one study showing a significant impact (P < 0.05) on AKI incidence. --- Explanation: Systematic review of 16 AKI genetic studies found APOE as the only replicated genetic association across multiple studies.


HGNC.SYMBOL:NR5A2

[PMID:39636799] [PARTIAL] rs184516290 (chr1:199814965:G:A), near the NR5A2 gene, chr1:199805801:T:TA, also near the NR5A2 gene, and rs117313146 (chr15:31999784:G:C), near the CHRNA7 gene, were associated with S-AKI at the suggestive level in all three models presented. --- Explanation: NR5A2 variants showed consistent suggestive association with sepsis-AKI but did not reach genome-wide significance threshold.


HGNC.SYMBOL:CHRNA7

[PMID:39636799] [PARTIAL] rs184516290 (chr1:199814965:G:A), near the NR5A2 gene, chr1:199805801:T:TA, also near the NR5A2 gene, and rs117313146 (chr15:31999784:G:C), near the CHRNA7 gene, were associated with S-AKI at the suggestive level in all three models presented. --- Explanation: CHRNA7 variant showed consistent suggestive association with sepsis-AKI across three models but did not reach genome-wide significance.


MONDO:0957553

[PMID:40555839] [SUPPORT] The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. --- Explanation: Overview defines neurodevelopmental delay as a core feature of HJS.

[PMID:41465181] [SUPPORT] Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58). --- Explanation: Systematic review of HJS type 2 showing 100% prevalence of DD/ID.


MONDO:0957553

[PMID:40555839] [SUPPORT] The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. --- Explanation: Language delay specifically highlighted as a core feature.


MONDO:0957553

[PMID:41465181] [SUPPORT] Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58). --- Explanation: Universal in HJS type 2 patients.

[PMID:39978342] [SUPPORT] The degree of intellectual disability was, on average, milder than in other HJS types. --- Explanation: HJS type 4 shows milder intellectual disability on average.


MONDO:0957553

[PMID:40555839] [SUPPORT] The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. --- Explanation: Prolonged hypotonia listed as a core feature.

[PMID:39978342] [SUPPORT] Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. --- Explanation: Hypotonia confirmed as common in HJS type 4.


MONDO:0957553

[PMID:40555839] [SUPPORT] The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. --- Explanation: Seizures listed as a core feature with high risk.

[PMID:41465181] [SUPPORT] Epilepsy occurred in 50.9% (29/57) --- Explanation: Quantifies epilepsy prevalence at ~51% in HJS type 2.


MONDO:0957553

[PMID:40555839] [SUPPORT] Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic. --- Explanation: Links macrocephaly to decreased PP2A activity and growth-promoting signaling.

[PMID:41465181] [SUPPORT] macrocephaly in 25.9% (15/58) --- Explanation: Quantifies macrocephaly at ~26% in HJS type 2.

[PMID:39201832] [SUPPORT] the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment. --- Explanation: Links macrocephaly to specific structural features of PPP2R5D variants affecting substrate recruitment.


MONDO:0957553

[PMID:41465181] [SUPPORT] Microcephaly was reported in 17.2% (10/58) --- Explanation: Quantifies microcephaly at ~17% in HJS type 2.


MONDO:0957553

[PMID:40340253] [SUPPORT] Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease. --- Explanation: ASD listed as a characteristic feature of HJS type 1.


MONDO:0957553

[PMID:41465181] [SUPPORT] structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent. --- Explanation: Corpus callosum abnormalities in 41% and ventriculomegaly in 32% of HJS type 2 patients.

[PMID:40781915] [SUPPORT] The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%). --- Explanation: Prenatal review showing corpus callosum abnormalities in 50% of prenatally detected HJS type 2 cases.


MONDO:0957553

[PMID:41465181] [SUPPORT] structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent. --- Explanation: Ventriculomegaly in ~32% of HJS type 2 patients.

[PMID:40781915] [SUPPORT] The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%). --- Explanation: Ventriculomegaly in 92% of prenatally detected HJS type 2 cases.


MONDO:0957553

[PMID:40340253] [SUPPORT] Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease. --- Explanation: Early-onset Parkinson disease listed as characteristic of HJS type 1.


MONDO:0957553

[PMID:41465181] [SUPPORT] dysmorphic features were present in 53.4% (31/58) --- Explanation: Systematic review quantifies dysmorphic features at ~53% in HJS type 2 patients.

[PMID:39978342] [SUPPORT] Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. --- Explanation: Mildly dysmorphic facial features reported in HJS type 4.


MONDO:0957553

[PMID:39728742] [SUPPORT] Haemangiomas have never been linked to the syndromic phenotype of the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme and the PI3K/AKT signalling pathway suggests the possible correlation between its dysfunction and activation of haemangiogenesis. --- Explanation: First report linking haemangiomas to PPP2R5D-related disorder, with mechanistic rationale via PI3K/AKT signaling.


MONDO:0957553

[PMID:40781915] [SUPPORT] The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%). --- Explanation: Congenital heart defects reported in 42% of prenatally detected HJS type 2 cases.


MONDO:0957553

[PMID:39201832] [INDIRECT EVIDENCE] [SUPPORT] Except for E420K and T536R, other missense variants impaired holoenzyme assembly. --- Explanation: In vitro experiments demonstrate that most PPP2R5D missense variants disrupt PP2A holoenzyme assembly.

[PMID:39978342] [INDIRECT EVIDENCE] [SUPPORT] All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). --- Explanation: Structural analysis showing PPP2R5C variants disrupt substrate or C-subunit binding in the PP2A complex.


MONDO:0957553

[PMID:40555839] [INDIRECT EVIDENCE] [SUPPORT] PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic. --- Explanation: Directly links PP2A dysfunction to overactivation of both PI3K/AKT/mTOR and RAS/MAPK growth kinase pathways.

[PMID:37572851] [INDIRECT EVIDENCE] [SUPPORT] We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity. --- Explanation: Phosphoproteomics of PPP2R5D E198K and E420K cells shows RPS6 hyperphosphorylation as shared convergent signaling alteration.

[PMID:37572851] [INDIRECT EVIDENCE] [SUPPORT] our data suggests ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K variant. --- Explanation: Demonstrates convergence of both ERK/MAPK and AKT pathways on mTORC1 in PPP2R5D variant cells, explaining why multiple growth pathways are co-activated.

[PMID:39728742] [INDIRECT EVIDENCE] [SUPPORT] There is evidence that the PP2A-PPP2R5D complex is involved in regulating the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial for several cellular processes, including the pathogenesis and progression of haemangiomas. --- Explanation: Documents PP2A-PPP2R5D regulation of PI3K/AKT signaling.


MONDO:0957553


MONDO:0957553

[PMID:40340253] [INDIRECT EVIDENCE] [SUPPORT] Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth. --- Explanation: iPSC study demonstrating neural progenitor hyperproliferation and neuronal overgrowth in PPP2R5D patients.

[PMID:40340253] [INDIRECT EVIDENCE] [SUPPORT] RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. --- Explanation: Transcriptomic evidence of disrupted neurodevelopmental pathways.

[PMID:40340253] [INDIRECT EVIDENCE] [SUPPORT] neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function. --- Explanation: Key finding confirming dominant-negative rather than haploinsufficiency mechanism.


MAXO:0000950

[PMID:40555839] [SUPPORT] Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found. --- Explanation: Notes that disease-modifying treatments are hypothetical and not yet available, so management remains supportive.


MAXO:0000930

[PMID:40555839] [SUPPORT] The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems. --- Explanation: Language delay is specifically emphasized, warranting speech therapy.


MAXO:0000079

[PMID:41465181] [SUPPORT] Recognition of recurrent hotspot variants and their phenotype associations facilitates diagnosis, prognosis, and genetic counseling. --- Explanation: Review emphasizes the role of genetic counseling based on variant-specific prognostication.


MAXO:0000058

[PMID:33482199] [SUPPORT] Rapamycin reduced cell size and dose-dependently reduced RPS6 phosphorylation in E420K-variant cells, suggesting that inhibition of mTOR1 can suppress both the observed RPS6 hyperphosphorylation and increased cell size. --- Explanation: In vitro evidence that rapamycin reverses molecular phenotypes in PPP2R5D E420K variant cells.

[PMID:37572851] [SUPPORT] We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity. --- Explanation: Shared RPS6 hyperphosphorylation across PPP2R5D variants provides a pharmacologically targetable biomarker.


MAXO:0001593

[PMID:40340253] [SUPPORT] antisense oligonucleotides (ASOs) were designed to selectively knock down the E198K allele, the most common disease-causing missense variant. The most effective ASOs reversed neurite outgrowth defects in patient-derived neurons. --- Explanation: Demonstrates allele-specific ASO approach reverses neuronal phenotypes in patient iPSC-derived neurons.


hgnc:9312

[PMID:40340253] [SUPPORT] neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function. --- Explanation: Confirms dominant-negative rather than loss-of-function mechanism.

[PMID:39201832] [SUPPORT] Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant. --- Explanation: Expands the variant spectrum for PPP2R5D.


hgnc:9302

[PMID:41465181] [SUPPORT] Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n = 5). --- Explanation: Identifies recurrent hotspot variants in PPP2R1A.


hgnc:9299

[PMID:40555839] [SUPPORT] dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome. --- Explanation: Overview defining PPP2CA as causative for HJS type 3.


hgnc:9311

[PMID:39978342] [SUPPORT] PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism. --- Explanation: Key mechanistic insight differentiating dominant-negative from haploinsufficiency.


MONDO:0957553

[PMID:40555839] [SUPPORT] recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic. --- Explanation: Overview confirms de novo dominant variants across PP2A subunits.


MONDO:0005459

[PMID:23829907] [SUPPORT] characteristic sleep-wake disturbances --- Explanation: The abstract lists sleep-wake disturbances as characteristic features.


MAXO:0000058

[PMID:40089378] [SUPPORT] A new oral drug, fexinidazole, became the first-line treatment for gambiense human African trypanosomiasis without severe meningo-encephalitic disease --- Explanation: The review describes fexinidazole as first-line therapy for gambiense HAT.


NCBITaxon:31285

[PMID:40089378] [SUPPORT] Human African trypanosomiasis or sleeping sickness is caused by infection with Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense parasites --- Explanation: The review identifies T. b. gambiense as a causative subspecies.


NCBITaxon:31286

[PMID:40089378] [SUPPORT] Human African trypanosomiasis or sleeping sickness is caused by infection with Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense parasites --- Explanation: The review identifies T. b. rhodesiense as a causative subspecies.


MONDO:0007739

[PMID:24176425] [SUPPORT] Huntington disease (HD) is an autosomal dominant, adult-onset, progressive neurodegenerative disease characterized by the triad of abnormal movements (typically chorea), cognitive impairment, and psychiatric problems. --- Explanation: The reference clearly states that chorea is a characteristic abnormal movement in Huntington's Disease.

[PMID:36049455] [SUPPORT] Chorea is one of the major manifestations of Huntington's disease. --- Explanation: This reference confirms that chorea is a major manifestation of Huntington's Disease.

[PMID:31707371] [SUPPORT] BACKGROUND: Anosognosia, or unawareness of illness of deficits, has been observed in Huntington's disease (HD) in relation to motor and cognitive signs and symptoms. Most studies of awareness in HD have used self-report questionnaire methodology rather than asking patients to report on their symptoms in real-time. The two studies in which patients were asked about their chorea in real-time had small sample sizes and only examined patients early in disease progression. --- Explanation: The reference mentions chorea in the context of Huntington's Disease, supporting the statement.

[PMID:6446233] [SUPPORT] Huntington's disease (chorea) is characterized by abnormal movements and dementia. --- Explanation: This reference directly associates Huntington's Disease with chorea.

[PMID:32699773] [SUPPORT] Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder with a progressive decline in cognitive, motor, and psychological function. Chorea tends to be the most common associated movement disorder, although other variants of several abnormal movements are also seen. --- Explanation: The reference states that chorea is the most common associated movement disorder in Huntington's Disease.


MONDO:0007739


MONDO:0007739

[PMID:7620118] [INDIRECT EVIDENCE] [SUPPORT] Early in 1993, an unstable, expanded trinucleotide repeat in a novel gene of unknown function was identified on HD chromosomes. This discovery unleased a flurry of experimentation that has established the expanded CAG repeat the almost universal cause of the characteristic neurologic symptoms and pathology of this neurodegenerative disorder of midlife onset. --- Explanation: The reference confirms that an expanded CAG repeat in the HTT gene is the cause of Huntington's Disease.

[PMID:35395060] [INDIRECT EVIDENCE] [SUPPORT] Huntington's disease (HD) is caused by an expansion of the CAG trinucleotide repeat domain in the huntingtin gene that results in expression of a mutant huntingtin protein (mHTT) containing an expanded polyglutamine tract in the amino terminus. --- Explanation: The literature clearly states that HD is caused by an expanded CAG repeat in the HTT gene, leading to a mutant huntingtin protein with an abnormal polyglutamine tract.

[PMID:27529325] [INDIRECT EVIDENCE] [SUPPORT] Huntington's disease (HD) belongs to the group of inherited polyglutamine (PolyQ) diseases caused by an expanded CAG repeat in the coding region of the Huntingtin (HTT) gene that results in an elongated polyQ stretch. --- Explanation: This reference supports the statement by specifying that HD is caused by an expanded CAG repeat in the HTT gene, leading to an elongated polyglutamine stretch.

[PMID:33579866] [INDIRECT EVIDENCE] [SUPPORT] Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. --- Explanation: The reference supports the statement, confirming that HD is caused by an expanded CAG repeat in the HTT gene.

[PMID:31398342] [INDIRECT EVIDENCE] [SUPPORT] Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. --- Explanation: This reference supports the statement by discussing the role of uninterrupted CAG repeats in the HTT gene in the development of HD.


MONDO:0007739

[PMID:35319359] [INDIRECT EVIDENCE] [SUPPORT] Pathogenesis of HD involves cleavage of the huntingtin protein followed by the neuronal accumulation of its aggregated form. --- Explanation: The literature supports that the pathogenesis of Huntington's Disease involves the accumulation of aggregated mutant huntingtin protein, leading to neuronal dysfunction and death.

[PMID:12657365] [INDIRECT EVIDENCE] [SUPPORT] The initial and primary target of degeneration in HD is the striatal medium spiny GABAergic neuron, and by end stages of the disease up to 95% of these neurons are lost. --- Explanation: This reference supports the statement by highlighting the primary degeneration of neurons in the striatum due to Huntington's Disease.

[PMID:31813995] [INDIRECT EVIDENCE] [SUPPORT] Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. --- Explanation: This literature supports the statement by confirming that mutant huntingtin protein aggregation leads to neurotoxicity, particularly in the striatum.

[PMID:23423362] [INDIRECT EVIDENCE] [SUPPORT] Evaluation of postmortem HD tissue indicates that the most prominent cell loss occurs in cerebral cortex and striatum, forebrain regions in which cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs) are the most affected. --- Explanation: This reference supports the statement by indicating significant neuronal loss in the striatum and cerebral cortex in Huntington's Disease.

[PMID:24048953] [INDIRECT EVIDENCE] [SUPPORT] Huntington's disease is caused by the expansion of a polyglutamine repeat (>37 glutamines) in the disease protein huntingtin, which results in preferential neuronal loss in distinct brain regions. --- Explanation: The literature supports the statement by confirming that mutant huntingtin protein causes neuronal loss in specific brain regions, including the striatum and cerebral cortex.


MONDO:0007739

[PMID:38776957] [INDIRECT EVIDENCE] [SUPPORT] We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. --- Explanation: The study identifies upregulation of glutamate receptors in medium spiny neurons, supporting the idea of excitotoxicity due to overactivation of these receptors leading to neuronal damage.

[PMID:1464368] [INDIRECT EVIDENCE] [SUPPORT] Excitotoxicity refers to neuronal cell death caused by activation of excitatory amino acid receptors. A substantial body of evidence has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurologic diseases. --- Explanation: This reference explains the concept of excitotoxicity and supports the idea that overactivation of glutamate receptors can lead to neuronal damage.

[PMID:7590394] [INDIRECT EVIDENCE] [SUPPORT] Our results indicated that elevated glutamate concentrations (15 mM, 1.5 mM, and 150 microM glutamate in perfusing solutions) would significantly increased both the concentrations of 2,3 and 2,5 DHBA. --- Explanation: The study provides direct evidence that elevated glutamate levels increase the formation of hydroxyl radicals, implying oxidative stress induced by excitotoxicity, which supports the statement.

[PMID:19805493] [INDIRECT EVIDENCE] [SUPPORT] Induction of striatal excitotoxicity in CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. --- Explanation: This study shows that excitotoxicity induced in the striatum leads to medium spiny neuron degeneration, supporting the idea of excitotoxicity causing neuronal damage in Huntington's Disease.


MONDO:0007739

[PMID:19622387] [INDIRECT EVIDENCE] [SUPPORT] Nonetheless, it is becoming increasingly clear that alterations in mitochondrial function play key roles in the pathogenic processes in HD. The net result of these events is compromised energy metabolism and increased oxidative damage, which eventually contribute to neuronal dysfunction and death. --- Explanation: Supports the pathophysiology entry by directly linking mitochondrial dysfunction in HD to compromised energy metabolism, oxidative damage, and neuronal death.

[PMID:23602910] [INDIRECT EVIDENCE] [SUPPORT] There is strong evidence that mitochondrial dysfunction results in neurodegeneration and may contribute to the pathogenesis of Huntington's disease (HD). Studies over the past few years have implicated an impaired function of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha (PGC-1alpha), a transcriptional master coregulator of mitochondrial biogenesis, metabolism, and antioxidant defenses, in causing mitochondrial dysfunction in HD. --- Explanation: Supports the mitochondrial dysfunction mechanism by connecting impaired PGC-1alpha activity to defective mitochondrial biogenesis, metabolism, and antioxidant defense in HD.


MONDO:0007739

[PMID:11839795] [INDIRECT EVIDENCE] [SUPPORT] In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. --- Explanation: In vivo evidence from HD transgenic mice showing that Sp1 binds soluble mutant huntingtin, supporting the sequestration mechanism.

[PMID:11839795] [INDIRECT EVIDENCE] [SUPPORT] Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. --- Explanation: Cell culture experiments demonstrating that mutant huntingtin suppresses Sp1-regulated transcription.

[PMID:11264541] [INDIRECT EVIDENCE] [SUPPORT] We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. --- Explanation: HD cell culture models showing CBP depletion from its normal nuclear location and sequestration into polyglutamine aggregates.

[PMID:11264541] [INDIRECT EVIDENCE] [SUPPORT] We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. --- Explanation: HD transgenic mice confirming CBP sequestration into polyglutamine aggregates in vivo.

[PMID:11264541] [INDIRECT EVIDENCE] [SUPPORT] We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. --- Explanation: Human HD postmortem brain tissue showing CBP depletion and sequestration into polyglutamine aggregates.

[PMID:12881722] [INDIRECT EVIDENCE] [SUPPORT] aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. We show that wild-type huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. --- Explanation: Human postmortem brain data showing aberrant nuclear REST/NRSF accumulation and reduced huntingtin-REST/NRSF interaction in HD.

[PMID:12881722] [INDIRECT EVIDENCE] [SUPPORT] loss of expression of NRSE-controlled neuronal genes is shown in cells, mice and human brain with Huntington disease. --- Explanation: Mouse model data confirming loss of NRSE-controlled gene expression in HD, corroborating the REST/NRSF dysregulation mechanism.

[PMID:12881722] [INDIRECT EVIDENCE] [SUPPORT] Wild-type huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. We show that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF), the transcription factor that binds to NRSE. --- Explanation: Cell-based experiments showing wild-type huntingtin sequesters REST/NRSF in the cytoplasm to permit BDNF transcription, a function lost with the mutant protein.


MAXO:0000058

[PMID:24366610] [SUPPORT] Tetrabenazine is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. --- Explanation: This reference confirms that tetrabenazine is used to manage chorea in Huntington's Disease by depleting dopamine.

[PMID:20869622] [SUPPORT] Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntington's disease. --- Explanation: This reference confirms that tetrabenazine depletes monoamines, including dopamine, to manage chorea in Huntington's Disease.

[PMID:20442355] [SUPPORT] Tetrabenazine binds reversibly to the type 2 vesicular monoamine transporters and has been shown to inhibit monoamine uptake in presynaptic vesicles, resulting in monoamine depletion. --- Explanation: This reference supports that tetrabenazine depletes dopamine to manage chorea in Huntington's Disease.

[PMID:27819145] [SUPPORT] Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD)... --- Explanation: This reference confirms that tetrabenazine, a VMAT2 inhibitor, is used to treat chorea in Huntington's Disease by depleting dopamine.


CHEBI:9467

[PMID:24366610] [INDIRECT EVIDENCE] [SUPPORT] Tetrabenazine is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. --- Explanation: This reference confirms that tetrabenazine is used to manage chorea in Huntington's Disease by depleting dopamine.

[PMID:20869622] [INDIRECT EVIDENCE] [SUPPORT] Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntington's disease. --- Explanation: This reference confirms that tetrabenazine depletes monoamines, including dopamine, to manage chorea in Huntington's Disease.

[PMID:20442355] [INDIRECT EVIDENCE] [SUPPORT] Tetrabenazine binds reversibly to the type 2 vesicular monoamine transporters and has been shown to inhibit monoamine uptake in presynaptic vesicles, resulting in monoamine depletion. --- Explanation: This reference supports that tetrabenazine depletes dopamine to manage chorea in Huntington's Disease.

[PMID:27819145] [INDIRECT EVIDENCE] [SUPPORT] Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD)... --- Explanation: This reference confirms that tetrabenazine, a VMAT2 inhibitor, is used to treat chorea in Huntington's Disease by depleting dopamine.


MAXO:0000058

[PMID:27534434] [SUPPORT] In clinical practice antipsychotics represent the first choice in the management of chorea in the presence of psychiatric symptoms... --- Explanation: The literature states that antipsychotics are used to manage psychiatric symptoms in Huntington's Disease.

[PMID:16383221] [SUPPORT] According to clinical observation, HD patients with psychiatric symptoms respond to standard pharmacotherapy. --- Explanation: The literature supports the use of pharmacotherapy, which includes antipsychotic medications, for psychiatric symptoms in Huntington's Disease.

[PMID:36496108] [SUPPORT] Several lines of evidence suggest a possible role of risperidone via the antagonistic effect of Dopamine D2 and 5HT-receptor in different neurological diseases like cognitive dysfunction of schizophrenia, neuroinflammation, Huntington's disease... --- Explanation: Risperidone, an antipsychotic, is mentioned as having a role in treating psychiatric symptoms in Huntington's Disease.


MAXO:0000058

[PMID:18394562] [SUPPORT] Several classes of medications have been used to ameliorate the various symptoms of HD, including typical and atypical neuroleptics, dopamine depleters, antidepressants... --- Explanation: The abstract mentions that antidepressants, which include SSRIs, are used to manage symptoms in Huntington's Disease.

[PMID:22119091] [SUPPORT] Cross-sectionally, suicidal mutation carriers were more likely to use antidepressants (odds ratio=5.3)... --- Explanation: The use of antidepressants, which can include SSRIs, is associated with managing depressive symptoms in Huntington's Disease.


MAXO:0000011

[PMID:31907286] [SUPPORT] There is strong evidence to support physical therapy interventions to improve fitness, motor function, and gait in persons with HD. --- Explanation: The review provides strong evidence that physical therapy interventions improve fitness, motor function, and gait in people with Huntington's Disease, supporting the statement that physical therapy helps maintain mobility and function.

[PMID:31177235] [SUPPORT] Prior Huntington''s disease (HD) studies suggest ancillary services improve motor symptoms, cognition, mood, and quality of life. --- Explanation: The study indicates that ancillary services, which include physical therapy, improve motor symptoms in HD patients, supporting the statement that physical therapy helps maintain mobility and function.

[PMID:25062860] [SUPPORT] TUG (beta 0.46, CI 0.20-3.47), BBS (beta -0.35, CI -2.10-0.14), and TMT (beta -0.45, CI -3.14-0.64) were good disease-specific mobility measures. --- Explanation: The study identifies specific mobility measures that are effective for assessing and optimizing mobility in HD patients, supporting the statement that physical therapy helps maintain mobility and function.


MAXO:0000077

[PMID:28983422] [PARTIAL] SLPs play an important role in the evaluation and management of dysarthria and dysphagia. --- Explanation: The literature indicates that speech-language pathologists (SLPs) play a significant role in managing dysarthria and dysphagia in patients with hyperkinetic disorders, including Huntington's Disease. However, it does not explicitly state that speech therapy helps manage these conditions in HD specifically.

[PMID:33577706] [PARTIAL] Findings shed a light on everyday communication challenges faced by people with HD and their professional caregivers, and the lack of implementation of communication aids in this group. --- Explanation: The literature highlights the importance of including speech and language therapists in the care of HD patients, indicating a supportive role. However, it does not provide explicit evidence that speech therapy directly helps manage dysarthria and dysphagia in HD.

[PMID:31989345] [NO_EVIDENCE] The impact of pharmacological and rehabilitative treatments on dysphagia in HD has been little studied in literature. --- Explanation: The literature states that the impact of rehabilitative treatments, including speech therapy, on dysphagia in HD has been minimally studied, providing no clear evidence of its efficacy.


MAXO:0000011

[PMID:28947114] [PARTIAL] Lifestyle factors, such as activity level and exercise, as well as specific motor training may be helpful in managing the functional sequelae of HD and possibly slowing disease progression. --- Explanation: The literature suggests that rehabilitation interventions, including motor training, can help manage functional abilities in HD, which implies a supportive role in daily living activities. However, it does not explicitly mention occupational therapy or daily living activities directly.

[PMID:36055643] [PARTIAL] This objective burden increased with higher functional loss of the HD individual and with more severe cognitive-behavioral disorders. --- Explanation: This study discusses the burden on informal caregivers and the functional loss in HD individuals, indicating a need for supportive roles, which could include occupational therapy. However, it does not explicitly mention occupational therapy.

[PMID:31177235] [SUPPORT] Prior Huntington's disease (HD) studies suggest ancillary services improve motor symptoms, cognition, mood, and quality of life but frequency of use and clinicalcharacteristics are unclear. --- Explanation: The literature explicitly mentions that ancillary services, which include occupational therapy, improve various aspects of life for HD patients, indicating a supportive role in daily living activities.


MAXO:0000079


HGNC.SYMBOL:HTT

[PMID:27188817] [SUPPORT] Huntington disease is devastating to patients and their families - with autosomal dominant inheritance... The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin. --- Explanation: The literature explicitly states that Huntington's disease is caused by an expanded CAG trinucleotide repeat in the HTT gene and is inherited in an autosomal dominant manner.

[PMID:33579864] [SUPPORT] Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. --- Explanation: This reference confirms that Huntington's disease is caused by the expansion of the HTT CAG repeat and follows an autosomal dominant inheritance pattern.

[PMID:31820322] [SUPPORT] Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. --- Explanation: This source supports the statement by indicating that Huntington's disease is an autosomal dominant disorder caused by a CAG expansion in the HTT gene.

[PMID:37863037] [SUPPORT] Among the CAG/polyQ repeat diseases are Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), in which the expansions are within widely expressed proteins. Although both HD and SCA1 are autosomal dominantly inherited... --- Explanation: This reference supports the statement by confirming that Huntington's disease is among the CAG repeat diseases and is autosomal dominantly inherited.

[PMID:33579866] [SUPPORT] Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. --- Explanation: This source supports the statement by confirming that Huntington's disease is caused by an expanded CAG repeat in the HTT gene and follows an autosomal dominant inheritance pattern.

[PMID:36352624] [SUPPORT] Huntington's Disease (HD) is an autosomal dominant, progressive neuropsychiatric illness caused by CAG repeat expansion. --- Explanation: This reference supports the statement by confirming that Huntington's disease is an autosomal dominant disorder caused by CAG repeat expansion.

[PMID:31263285] [SUPPORT] Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT)... --- Explanation: This source supports the statement by confirming that Huntington's disease is caused by a CAG trinucleotide expansion in the HTT gene and follows an autosomal dominant inheritance pattern.

[PMID:31491822] [SUPPORT] The expression of the HTT CAG repeat expansion mutation causes neurodegeneration in Huntington's disease (HD). --- Explanation: This reference supports the statement by confirming that the HTT CAG repeat expansion causes neurodegeneration in Huntington's disease.

[PMID:26439718] [SUPPORT] Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in the first exon of the Huntingtin (HTT) gene. --- Explanation: This source supports the statement by confirming that Huntington's disease is caused by the expansion of a CAG trinucleotide repeat in the HTT gene.

[PMID:28832564] [SUPPORT] Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT... --- Explanation: This reference supports the statement by confirming that Huntington's disease is caused by the expansion of a CAG trinucleotide repeat in the HTT gene and is autosomal dominant.


HGNC.SYMBOL:MSH3


HGNC.SYMBOL:MLH1


HGNC.SYMBOL:PMS1


HGNC.SYMBOL:PMS2


HGNC.SYMBOL:LIG1


HGNC.SYMBOL:PPARGC1A


HGNC.SYMBOL:SLC1A2


HGNC.SYMBOL:BDNF


HGNC.SYMBOL:NTRK2


HGNC.SYMBOL:DRD1


HGNC.SYMBOL:DRD2


HGNC.SYMBOL:SQSTM1


MONDO:0021187

[DOI:10.3390/ijms25126364] [SUPPORT] the higher the plasma concentrations in TGs, the higher the incidence and prevalence of death, myocardial infarction, and stroke. --- Explanation: Confirms the dose-dependent relationship between elevated triglycerides and adverse cardiovascular outcomes.


MONDO:0021187

[PMID:28444290] [SUPPORT] any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C --- Explanation: Establishes that cumulative LDL exposure drives atherosclerosis, explaining why familial hyperlipidemia with lifelong elevation causes premature disease.


MONDO:0021187


MONDO:0021187

[DOI:10.3390/ijms25126364] [SUPPORT] The risk for coronary heart diseases varies from 57 to 76% in patients with hypertriglyceridemia. --- Explanation: Quantifies the high coronary heart disease risk in patients with hyperlipidemia.


MONDO:0021187

[PMID:28444290] [SUPPORT] Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD --- Explanation: Establishes the dose-dependent association between LDL-C exposure and ASCVD risk.

[DOI:10.5114/aoms/174743] [SUPPORT] almost 4 million deaths per year are attributed to LDL-C --- Explanation: Demonstrates the massive global burden attributable to elevated LDL cholesterol.


MONDO:0021187

[DOI:10.1038/s41467-024-46336-2] [INDIRECT EVIDENCE] [SUPPORT] Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. --- Explanation: Confirms that LDL receptor degradation by PCSK9 leads to impaired LDL clearance and elevated LDL-C levels.

[PMID:28444290] [INDIRECT EVIDENCE] [SUPPORT] Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. --- Explanation: The EAS consensus confirms that LDL receptor mutations cause elevated LDL-C and dose-dependent ASCVD risk.


MONDO:0021187

[DOI:10.1038/s41467-024-46336-2] [INDIRECT EVIDENCE] [SUPPORT] PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. --- Explanation: Demonstrates that PCSK9 has LDLR-independent pro-inflammatory functions, contributing to atherosclerosis beyond its role in LDL receptor degradation.

[DOI:10.1038/s41467-024-46336-2] [INDIRECT EVIDENCE] [SUPPORT] Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. --- Explanation: Identifies the CAP1-mediated signaling pathway through which PCSK9 promotes inflammation and foam cell formation.


MONDO:0021187

[DOI:10.1186/s12944-023-01993-y] [INDIRECT EVIDENCE] [SUPPORT] Preclinical investigations have revealed that interventions targeting VLDL production or promoting VLDL metabolism, independent of the LDL receptor, can potentially decrease cholesterol levels and provide therapeutic benefits. --- Explanation: Confirms that VLDL production is a key therapeutic target in hyperlipidemia and that VLDL overproduction contributes to elevated cholesterol levels.


MONDO:0021187

[DOI:10.1007/s11883-023-01080-8] [INDIRECT EVIDENCE] [SUPPORT] ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia --- Explanation: Confirms the central role of ApoC-III in triglyceride metabolism dysregulation and its broader cardiometabolic effects.

[DOI:10.1007/s11883-023-01080-8] [INDIRECT EVIDENCE] [SUPPORT] the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention --- Explanation: Validates ApoC-III as a key pathogenic molecule in hypertriglyceridemia.


MONDO:0021187

[PMID:30165986] [INDIRECT EVIDENCE] [SUPPORT] Because atherogenic lipoproteins play a central causal role in the initiation and progression of atherosclerosis, maintaining optimal lipid levels is necessary to achieve ideal cardiovascular health. --- Explanation: Supports oxLDL-associated lipoprotein burden as an initiating event in atherosclerosis.


MONDO:0021187

[DOI:10.3390/nu16132156] [INDIRECT EVIDENCE] [SUPPORT] Disruption in any of these steps results in pathophysiological abnormalities such as dyslipidemia, obesity, insulin resistance, inflammation, atherosclerosis, peripheral artery disease, and cardiovascular diseases. --- Explanation: Supports inflammation-coupled transition from lipid imbalance to arterial immune-cell pathology.


MONDO:0021187

[DOI:10.1038/s41467-024-46336-2] [INDIRECT EVIDENCE] [SUPPORT] Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. --- Explanation: Supports enhanced oxidized-LDL uptake as a proximate mechanism for foam cell formation.


MONDO:0021187

[DOI:10.3390/nu16132156] [INDIRECT EVIDENCE] [SUPPORT] Disruption in any of these steps results in pathophysiological abnormalities such as dyslipidemia, obesity, insulin resistance, inflammation, atherosclerosis, peripheral artery disease, and cardiovascular diseases. --- Explanation: Confirms the pathological link between lipoprotein dysregulation and atherosclerosis.

[PMID:28444290] [INDIRECT EVIDENCE] [SUPPORT] Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD. --- Explanation: The definitive EAS consensus statement establishing LDL as a causal factor in atherosclerotic cardiovascular disease.


MAXO:0000058

[DOI:10.3390/nu16132156] [SUPPORT] Several medications are available for the treatment of dyslipoproteinemia. These include statins, fibrates, ezetimibe, niacin, PCSK9 inhibitors, evinacumab --- Explanation: Lists statins as first-line pharmacotherapy for dyslipoproteinemia.

[DOI:10.5114/aoms/174743] [SUPPORT] In 2023 there are still even 75% of patients over the LDL-C target, and hypercholesterolemia is the most common and the worst monitored CVD risk factor. --- Explanation: Highlights the ongoing need for effective statin therapy given high rates of uncontrolled LDL-C.


MAXO:0000058

[DOI:10.1038/s41467-024-46336-2] [SUPPORT] Its blockers have emerged as promising therapeutics for cardiovascular diseases. --- Explanation: Confirms the therapeutic value of PCSK9 inhibition in cardiovascular disease management.


MAXO:0000058


MAXO:0000088


MAXO:0000058

[DOI:10.1186/s12944-024-02297-5] [SUPPORT] Olezarsen is a GalNAc3-conjugated, hepatic-targeted antisense oligonucleotide that lowers apolipoprotein C-III (apoC-III) and triglyceride levels. --- Explanation: Describes the mechanism and clinical efficacy of the ApoC-III targeting antisense approach.

[DOI:10.1186/s12944-024-02297-5] [SUPPORT] In the MD cohort, at Day 92 the percentage reduction in apoC-III/TG was − 81.6/ − 73.8% vs − 17.2/ − 40.8% reduction in placebo. --- Explanation: Demonstrates substantial triglyceride reduction achieved with ApoC-III inhibition in clinical trials.


hgnc:6547

[PMID:28444290] [SUPPORT] Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD --- Explanation: Confirms that LDLR loss-of-function mutations are causal in familial hypercholesterolemia and ASCVD.


hgnc:20001

[DOI:10.1038/s41467-024-46336-2] [SUPPORT] Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. --- Explanation: Confirms the canonical mechanism of PCSK9-mediated LDL receptor degradation.


hgnc:603

[PMID:22417841] [SUPPORT] Autosomal dominant hypercholesterolemia (ADH) is commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene (LDLR), in the apolipoprotein B-100 gene (APOB), or in the proprotein convertase subtilisin kexine 9 gene (PCSK9). --- Explanation: Directly supports APOB mutation involvement in autosomal dominant hypercholesterolemia.


hgnc:6677


hgnc:613


hgnc:611

[DOI:10.1007/s11883-023-01080-8] [SUPPORT] ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve --- Explanation: Confirms the pathogenic role of APOC3 in cardiovascular disease.


MONDO:0021187

[DOI:10.3390/nu16132156] [SUPPORT] Disruption in any of these steps results in pathophysiological abnormalities such as dyslipidemia, obesity, insulin resistance, inflammation, atherosclerosis, peripheral artery disease, and cardiovascular diseases. --- Explanation: Dyslipidemia, including elevated total cholesterol, is a primary manifestation of lipoprotein metabolism disruption.


MONDO:0021187

[PMID:28444290] [SUPPORT] Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD. --- Explanation: Elevated LDL cholesterol is the central biochemical abnormality in hyperlipidemia and causally linked to ASCVD.


MONDO:0021187

[PMID:30021845] [SUPPORT] Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and nuclear magnetic resonance-derived measures of HDL, were significant risk determinants. --- Explanation: Directly supports reduced HDL as part of the clinically relevant atherogenic dyslipidemia signature.

[PMID:40489011] [SUPPORT] Decreased serum high-density-lipoprotein-cholesterol (HDL-C), HDL particles, and cell-cholesterol-efflux-capacity have all been associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. --- Explanation: Summarizes independent HDL-related associations with ASCVD risk.


MONDO:0021187

[DOI:10.1007/s11883-023-01080-8] [SUPPORT] ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia --- Explanation: ApoC-III is elevated in hypertriglyceridemia and contributes to TRL accumulation.


MONDO:0001302

[PMID:31472880] [PARTIAL] Hypertensive heart disease includes the development of diastolic dysfunction, left ventricular hypertrophy, and heart failure with preserved and reduced ejection fraction. The development of heart failure can occur because of complications of ischemic heart disease or from progression of diastolic dysfunction to heart failure with preserved ejection fraction degenerating to a dilated heart with systolic dysfunction or heart failure with reduced ejection fraction. --- Explanation: The reference mentions heart failure as a frequent complication of hypertensive heart disease, but it does not specifically address dyspnea.

[PMID:15950133] [PARTIAL] Dyspnea and leg effort are the major symptoms limiting exercise in healthy subjects and in patients with a variety of respiratory disorders. --- Explanation: While the reference discusses dyspnea as a symptom that limits exercise tolerance, it is not specific to hypertensive heart disease.

[PMID:37345800] [SUPPORT] Ventilatory efficiency is impaired people with hypertension without a diagnosis of heart failure versus normotensive individuals. --- Explanation: This reference implies that dyspnea could be an issue in hypertensive patients, which could lead to reduced exercise tolerance.

[PMID:26569571] [PARTIAL] Pulmonary hypertension (PH) due to left-sided heart disease (LSHD) is a common and disconcerting occurrence. For example, both heart failure (HF) with preserved and reduced ejection fraction (HFpEF and HFrEF) often lead to PH as a consequence of a chronic elevation in left atrial filling pressure. --- Explanation: It mentions heart failure and its link to dyspnea indirectly through pulmonary hypertension but does not focus on hypertensive heart disease specifically.


MONDO:0001302

[PMID:35061769] [SUPPORT] Hypertension was found in 45% of patients. Hypertensive patients were older, with a higher SIS, calcium score, and prevalence of comorbidities and statin therapy compared to the normotensive (all p<0.05). --- Explanation: Description supports the presence of cardiovascular phenotypes linked to hypertensive heart disease, such as varying levels of coronary artery involvement.

[PMID:37861255] [SUPPORT] PH is more than a single clinical entity due to its complex mechanism in which more than one subgroup may develop over time in the same patient. This complex mechanism challenges us when diagnosing the patient and faces us with life-threatening complications. --- Explanation: Pulmonary hypertension can be linked to hypertensive heart disease and exhibits complex cardiovascular phenotypes, including potential complications visible in diagnostic criteria.


MONDO:0001302

[PMID:34809918] [PARTIAL] PH due to LHD is associated with negative impact on outcomes in addition to worse symptoms and exercise capacity. --- Explanation: While this supports the cardiovascular phenotype in the context of arrhythmias, it does not specifically mention palpitations or syncope as sequelae of hypertensive heart disease.

[PMID:36202538] [PARTIAL] Evaluation of cardiac phenotypes in secondary hypertension provides a unique opportunity to study underlying hormonal and biochemical mechanisms affecting the heart. --- Explanation: This implies a variety of cardiac phenotypes can be seen in hypertension but does not explicitly list arrhythmias, palpitations, or syncope.


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[PMID:19863866] [SUPPORT] Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. --- Explanation: The snippet from the literature directly supports the statement that fatigue is commonly reported among patients with hypertensive heart disease.


MONDO:0001302

[PMID:2959621] [PARTIAL] Chest pain is a common complaint among hypertensive patients. --- Explanation: The literature supports that chest pain is common among hypertensive patients, but it does not specify the frequency as 'occasional'.

[PMID:30066227] [PARTIAL] Uncontrolled hypertension is one of the most common determinant for the persistently high burden of cardiovascular (CV) disease, mostly including coronary artery disease (CAD) and hospital admissions due to acute coronary events. --- Explanation: The literature supports that hypertension is linked to coronary artery disease, which can present with chest pain, but it does not specify the frequency as 'occasional'.

[PMID:20932116] [PARTIAL] Evidence of a link between headache symptoms and cardiovascular disease has rapidly grown in recent years and it is of utmost importance for the cardiologist and neurologist to be aware of this intimate connection. --- Explanation: The literature supports the link between cardiovascular disease and symptoms such as chest pain, but it does not specify the frequency as 'occasional'.


MONDO:0001302

[PMID:31472889] [PARTIAL] Hypertensive heart disease can manifest as cardiac arrhythmias. Supraventricular and ventricular arrhythmias may occur in the hypertensive patients. --- Explanation: The literature supports that hypertensive heart disease can manifest as arrhythmias, but it does not specifically address the frequency as 'occasional'.

[PMID:36519436] [PARTIAL] Hypertension is prevalent in >70% of atrial fibrillation patients. In turn, hypertensive patients have up to 73% greater likelihood of atrial fibrillation. --- Explanation: The literature supports the association between hypertension and atrial fibrillation but does not specify the frequency of arrhythmias in hypertensive heart disease as 'occasional'.


MONDO:0001302

[PMID:11419663] [SUPPORT] Essential treatment includes rapid initiation of pharmacologic agents to control hypertension. --- Explanation: This reference indicates that controlling hypertension is essential in the treatment of aortic dissection, supporting the notion that hypertension is a major risk factor for aortic dissection.

[PMID:25620633] [SUPPORT] In this review, we discuss cardiovascular hypertensive emergencies, including acute coronary syndrome, aortic dissection, congestive heart failure, and sympathomimetic hypertensive crises. --- Explanation: This reference discusses aortic dissection as a cardiovascular hypertensive emergency, supporting the statement that hypertension is a major risk factor for aortic dissection.

[PMID:25573747] [SUPPORT] A clinical profile of those at risk of dissection is emerging and includes the presence of congenital heart defects, aortic dilatation and hypertension. --- Explanation: This reference mentions hypertension as part of the clinical profile for those at risk of aortic dissection, supporting the statement.

[PMID:27873227] [PARTIAL] Even though arterial hypertension is commonly regarded as a predisposing condition for the development of thoracic aorta aneurysms, the role of blood pressure (BP) as determinant of aortic root enlargement is still controversial. --- Explanation: This reference acknowledges that hypertension is commonly regarded as a predisposing condition for aortic diseases but notes some controversy regarding its role, providing partial support.

[PMID:23993245] [SUPPORT] Similar to other acute cardiovascular events (e.g., acute myocardial infarction, sudden death, stroke, and pulmonary embolism) there is a growing body of evidence regarding temporal patterns in onset, characterized by circadian, seasonal and weekly variations for aortic aneurysms. --- Explanation: This reference discusses aortic dissection within the context of other cardiovascular events and mentions hypertension as a common underlying pathophysiologic mechanism, supporting the statement.


MONDO:0001302

[PMID:10645696] [SUPPORT] Hypertension is a leading cause of both stroke and heart disease. --- Explanation: The abstract explicitly states that hypertension is a leading cause of stroke, supporting the statement that hypertensive heart disease is occasionally associated with strokes.

[PMID:37980821] [SUPPORT] Hypertension... for IS only. --- Explanation: The abstract mentions hypertension as a risk factor for ischemic stroke, supporting the statement that hypertensive heart disease is occasionally associated with strokes.

[PMID:36990309] [SUPPORT] Hypertensive disorders of pregnancy are associated with a long-term risk for... ischemic stroke or hemorrhagic stroke in later life. --- Explanation: The abstract indicates a significant association between hypertensive disorders and stroke, supporting the statement that hypertensive heart disease is occasionally associated with strokes.

[PMID:29869130] [SUPPORT] Arterial hypertension represents the most important risk factor for ischemic and haemorrhagic stroke. --- Explanation: This abstract clearly supports the statement that hypertensive heart disease is occasionally associated with strokes.

[PMID:32224751] [SUPPORT] Risk factor modification plays a large role in stroke prevention. Strategies for early intervention, particularly for hypertension, are critical for reducing stroke morbidity and mortality. --- Explanation: The abstract supports the role of hypertension as a risk factor for stroke, aligning with the statement that hypertensive heart disease is occasionally associated with strokes.

[PMID:24080990] [SUPPORT] Apart from the well-known role of hypertension in cerebrovascular disease... an independent risk factor for stroke. --- Explanation: This abstract confirms the role of hypertension as a risk factor for stroke, supporting the statement that hypertensive heart disease is occasionally associated with strokes.


MONDO:0001302

[PMID:31472888] [NO_EVIDENCE] The authors discuss the natural history and pathogenesis of heart failure owing to hypertensive heart disease, reviewing the important role of left ventricular hypertrophy as the inciting process leading to diastolic dysfunction and heart failure with preserved ejection fraction. --- Explanation: The provided literature discusses the pathogenesis and progression of hypertensive heart disease but does not mention fatigue as a frequent symptom.

[PMID:29766272] [NO_EVIDENCE] The aim of this study was to evaluate the cardio-protective effects of different drug classes in treated pediatric hypertensive patients. --- Explanation: This study focuses on the effects of different antihypertensive drugs on pediatric patients and does not address fatigue as a symptom of hypertensive heart disease.

[PMID:28541499] [NO_EVIDENCE] Hypertension (HTN) is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease (CAD), stroke, peripheral artery disease and chronic renal failure. --- Explanation: The document discusses various complications of hypertension but does not mention fatigue as a frequent symptom of hypertensive heart disease.

[PMID:17593316] [NO_EVIDENCE] Heart rate is an independent risk factor for patients with cardiovascular disease, in particular with arterial hypertension, myocardial infarction, coronary artery disease and heart failure. --- Explanation: This article focuses on the role of heart rate in cardiovascular diseases but does not mention fatigue as a frequent symptom of hypertensive heart disease.

[PMID:23732143] [NO_EVIDENCE] Hypertension is strongly associated with overall cardiovascular risk. Increased blood pressure contributes to cardiovascular and cerebrovascular endpoints, such as myocardial infarction, heart failure, cardiovascular death and stroke. --- Explanation: The literature describes the risks associated with hypertension but does not mention fatigue as a frequent symptom of hypertensive heart disease.

[PMID:38597067] [NO_EVIDENCE] We now have compelling evidence for a key role of sympathetic overactivity in the pathogenesis and progression of hypertension and associated hypertension-mediated organ damage (such as endothelial dysfunction, arterial stiffness and left ventricular hypertrophy). --- Explanation: The literature discusses the role of sympathetic overactivity in hypertension and its complications but does not mention fatigue as a frequent symptom of hypertensive heart disease.


MONDO:0001302

[PMID:18677585] [SUPPORT] Hypertension and proteinuria are common risk factors for cardiovascular morbidity and mortality, as well as for the progression of renal disease. --- Explanation: The literature indicates that hypertension is associated with proteinuria and the progression of renal disease, supporting the statement that hypertension can cause and worsen kidney damage.

[PMID:1614065] [PARTIAL] The number of patients developing end-stage renal disease (ESRD) as a consequence of hypertension is increasing and accounts for 25% of new cases of ESRD in the United States. However, the diagnosis of hypertensive ESRD is one of exclusion and no pathologic data corroborate this classification. --- Explanation: While the literature suggests a link between hypertension and end-stage renal disease, it also notes that the diagnosis is often one of exclusion and lacks definitive pathologic data.

[PMID:7606639] [SUPPORT] The kidney can be considered as both culprit and victim in the hypertensive process. Deranged renal function contributes to the development of arterial hypertension and of secondary vascular damage at the glomerular and arteriolar level and accounts for the development of progressive nephrosclerosis. --- Explanation: This reference supports the statement by indicating that hypertension can lead to renal damage, including proteinuria and nephrosclerosis.

[PMID:20400279] [SUPPORT] With ongoing progression and glomerular extracapillary proliferation, tubulointerstitial damage occurs with consequent nephron loss and development of fibrotic lesions, finally resulting in terminal renal failure. --- Explanation: The literature supports the statement by discussing how glomerular injury, often exacerbated by conditions like hypertension, leads to further renal damage and proteinuria.


MONDO:0001302


MONDO:0001302

[PMID:11062603] [INDIRECT EVIDENCE] [SUPPORT] Sustained increase in arterial pressure causes left ventricular hypertrophy and adversely affects all myocardial compartments: myocytes, interstitium, and coronary vasculature. --- Explanation: The paper discusses how hypertension causes left ventricular hypertrophy and affects multiple myocardial compartments.

[PMID:36933415] [INDIRECT EVIDENCE] [SUPPORT] We computed both eccentric and concentric hypertrophy effects and tracked changes in the ventricle shape and wall thickness. --- Explanation: The study confirms that changes in wall thickness and ventricular shape due to hypertrophy reflect an adaptation to increased workload.

[PMID:10652906] [INDIRECT EVIDENCE] [SUPPORT] Left ventricular hypertrophy (LVH) is pathognomonic of HHD. --- Explanation: Left ventricular hypertrophy is directly associated with hypertensive heart disease and involves thickening of the heart muscle.

[PMID:37827810] [INDIRECT EVIDENCE] [SUPPORT] In case of hypertrophy, an increased influence of the dilating transmural fibre component might counteract systolic wall thickening, thereby counteract cardiac output. --- Explanation: The reference discusses the influence of hypertrophy on wall thickening and heart function.


MONDO:0001302

[PMID:37999643] [INDIRECT EVIDENCE] [SUPPORT] In response to increased peripheral resistance in hypertension, intensified mechanical stretch in the myocardium induces cardiomyocyte hypertrophy and fibroblast activation to withstand increased pressure overload. This changes the structure and function of the heart, leading to pathological cardiac remodeling and eventual progression to heart failure. --- Explanation: The activation of fibroblasts in response to hypertension and their role in cardiac remodeling aligns with the statement that chronic pressure overload stimulates fibroblasts to deposit excess collagen in the heart.

[PMID:33568808] [INDIRECT EVIDENCE] [SUPPORT] Diffuse myocardial fibrosis resulting from the excessive deposition of collagen fibres through the entire myocardium is encountered in a number of chronic cardiac diseases. This lesion results from alterations in the regulation of fibrillary collagen turnover by fibroblasts, facilitating the excessive deposition of type I and type III collagen fibres within the myocardial interstitium and around intramyocardial vessels. --- Explanation: This reference details how fibroblasts facilitate excessive collagen deposition in the myocardium, which supports the statement regarding cardiac fibrosis due to chronic pressure overload.

[PMID:2532916] [INDIRECT EVIDENCE] [SUPPORT] In left ventricular pressure overload a reactive interstitial fibrosis, having distinctive biochemical and structural features, is seen. This reactive fibrosis occurs in the absence of myocyte necrosis, is progressive in nature, and initially is an adaptive response that preserves the force generating capacity, or active (systolic) stiffness, of the hypertrophied myocardium. --- Explanation: The description of reactive interstitial fibrosis in response to pressure overload supports the statement about fibroblasts depositing excess collagen in the heart under chronic pressure overload conditions, leading to fibrosis and stiffening.

[PMID:10829097] [INDIRECT EVIDENCE] [SUPPORT] Mechanisms underlying risk associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) are discussed in this report and provide a rationale for understanding this very common and important cause of death from hypertension and its complications. Emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis from increased collagen deposition intramurally and perivascularly. --- Explanation: The mention of ventricular fibrosis due to increased collagen deposition supports the statement that chronic pressure overload results in fibroblasts depositing excess collagen, leading to cardiac fibrosis.

[PMID:33570899] [INDIRECT EVIDENCE] [SUPPORT] The differentiation of TH17 cells reflected the cardiac hypertrophy and remodeling response to hypertension-induced pressure overload, and it might be a potential inflammatory marker to predict the prognosis of hypertensive patients. --- Explanation: Although this snippet primarily focuses on TH17 cells, it indicates that remodeling due to hypertension includes elements of fibroblast activation and fibrosis.


MAXO:0000181

[PMID:15331316] [SUPPORT] Outcomes in HHD and HF are improved by antihypertensive drugs at any stage of the condition. --- Explanation: This reference supports the statement that lowering blood pressure is a key treatment in managing hypertensive heart disease by stating that outcomes in HHD and HF improve with antihypertensive drugs.

[PMID:32728994] [SUPPORT] Extensive evidence demonstrates that lowering blood pressure can substantially reduce the risk of atherosclerotic cardiovascular disease and death. --- Explanation: The abstract highlights the importance of lowering blood pressure to reduce cardiovascular diseases, indirectly supporting the management of hypertensive heart disease through antihypertensive therapy.

[PMID:31472890] [SUPPORT] Management of hypertension reduces cardiovascular outcomes among patients with diabetes. --- Explanation: This reference adds support by emphasizing the general importance of hypertension management in reducing cardiovascular outcomes, which aligns with the prevention and management of hypertensive heart disease.


MAXO:0000652

[PMID:2485024] [SUPPORT] There is evidence to suggest that angiotensin-converting enzyme (ACE) inhibitors can play an important role in protecting the heart during the various phases of evolution of hypertensive heart disease both acutely and on a long-term basis. --- Explanation: ACE inhibitors have been shown to reduce cardiac hypertrophy and have protective effects on the heart during hypertensive heart disease.

[PMID:19588327] [SUPPORT] ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85). --- Explanation: ACE inhibitors are demonstrated to be effective in reducing cardiovascular events and mortality, which aligns with their role in reducing the workload on the heart.

[PMID:31498767] [SUPPORT] Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used primarily to treat hypertension and are also useful for conditions such as heart failure and chronic kidney disease, independent of their effect on blood pressure. --- Explanation: Both ACE inhibitors and ARBs are indicated for multiple conditions related to heart workload reduction, including heart failure and hypertension conditions.

[PMID:26968600] [SUPPORT] Management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. --- Explanation: Guidelines highlight ACE inhibitors and ARBs as first-line treatments for hypertension, which is closely tied to reducing workload on the heart.


MAXO:0000186

[PMID:8651834] [SUPPORT] Beta-Blockers are widely used in cardiovascular medicine... Based on evidence showing reduced mortality and morbidity, beta-blockers are the cornerstone of therapy after acute myocardial infarction. --- Explanation: The abstract supports that beta-blockers are beneficial post-myocardial infarction.

[PMID:19615493] [SUPPORT] Today, in patients with acute or chronic coronary syndromes or with congestive heart failure, reducing heart rate is a generally accepted treatment modality. --- Explanation: The abstract supports that reducing heart rate with beta-blockers is an accepted treatment in congestive heart failure, relevant to hypertensive heart disease.

[PMID:20539841] [SUPPORT] One successful way of decreasing HR and cardiovascular mortality has been by utilizing beta-blockers... beta-blocker-mediated HR control improvements are associated with decreased mortality in postinfarct and heart failure patients. --- Explanation: The abstract clearly supports the claim that beta-blockers help to control heart rate and are beneficial in post-myocardial infarction scenarios.

[PMID:28402023] [SUPPORT] Combination of beta-blocker therapy with ET does not compromise the effect of training and instead promotes HRR and aerobic capacity improvement... However, chronic administration of beta-blocker therapy alone did not promote improvement in HRR or aerobic capacity. --- Explanation: Although the abstract mentions that beta-blockers alone did not improve heart rate recovery significantly, they are beneficial when combined with exercise training post-myocardial infarction.

[PMID:140280] [SUPPORT] Regardless of the level of arterial pressure, vasodilator drugs that lower arterial pressure may result in marked improvement in left ventricular performance and relief of symptoms of left ventricular failure. --- Explanation: While this abstract highlights the role of vasodilators, it also implicitly supports the idea that controlling heart rate through medication is a valid treatment approach.


MAXO:0000058

[PMID:24243991] [SUPPORT] Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. --- Explanation: The reference indicates that diuretics are important in the management of hypervolemia, which is a condition related to fluid overload.

[PMID:19863866] [SUPPORT] In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms. --- Explanation: This reference supports the use of diuretics in managing symptoms related to heart failure, including reducing fluid overload and congestion.

[PMID:35165832] [SUPPORT] soluble guanylate cyclase stimulators are new classes of chemical agents that... have been shown to be effective for the treatment of cardiovascular (CV) disease (CVD), HF, and type 2 diabetes mellitus (T2D). --- Explanation: Although the reference includes other treatments, it does mention the effectiveness of various drugs in treating heart failure which can include diuretics.

[PMID:35190215] [SUPPORT] Diuretics are the cornerstone of therapy for volume overload and comprise several classes whose mechanisms of action, pharmacokinetics, indications, and adverse effects are essential principles of nephrology. --- Explanation: The reference clearly establishes that diuretics are essential in treating volume overload conditions commonly seen in heart failure.

[PMID:38300391] [SUPPORT] Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF)... The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF... --- Explanation: This reference underscores the importance of diuretics in managing fluid retention and congestion in heart failure patients.


MAXO:0000058

[PMID:17362671] [SUPPORT] The vital importance of mineralocorticoid receptor antagonists for treating cardiovascular conditions has only been appreciated in the last decade. --- Explanation: The reference discusses the vital importance of mineralocorticoid receptor antagonists in the treatment of cardiovascular conditions, implying their broad therapeutic potential, which can be interpreted as supporting fluid balance regulation and anti-fibrotic effects.

[PMID:10904856] [SUPPORT] The competitive aldosterone receptor antagonist, spironolactone, was able to prevent fibrosis in both ventricles in either model of arterial hypertension irrespective of the development of left ventricular hypertrophy and hypertension. --- Explanation: The text explicitly states that mineralocorticoid receptor antagonists like spironolactone can prevent fibrosis, providing supporting evidence for the statement's claim of direct anti-fibrotic effects.

[PMID:35438025] [SUPPORT] All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 +/- 20 mg) and in the remaining 56% of subjects eplerenone was administered. --- Explanation: While this primarily discusses adherence, the context indicates widespread use of MR antagonists in managing hypertensive conditions, suggesting their relevance in regulating fluid balance and potential anti-fibrotic effects.

[PMID:25016402] [SUPPORT] Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. --- Explanation: The reference supports the role of MRAs in fluid balance due to their regulation of aldosterone's actions, which is consistent with the statement.

[PMID:28176630] [SUPPORT] Finerenone, a non-steroidal mineralocorticoid receptor antagonist... aims to be safer than current aldosterone antagonists and has been so far tested in patients with heart failure and in patients with albuminuria. --- Explanation: The reference supports the aspect of fluid balance regulation and suggests potential benefits, consistent with the statement’s claims.


MAXO:0000088

[PMID:3882040] [PARTIAL] These therapies include weight reduction; sodium restriction; potassium, calcium, and magnesium supplementation; other dietary changes; exercise; relaxation; and moderation of alcohol use. Such therapies have been inadequately used, in part because of a lack of confidence in their effectiveness and overconfidence in the effectiveness and safety of drug therapy. --- Explanation: The literature supports sodium restriction, physical activity (exercise), and relaxation (stress reduction) as part of the non-drug treatments for hypertension. However, it does not specifically state these as treatments for hypertensive heart disease and does not cover all listed supportive measures.

[PMID:20937450] [PARTIAL] Optimal antihypertensive therapy in the setting of therapeutic lifestyle changes is crucial in the prevention and control of HHD. --- Explanation: This literature mentions that therapeutic lifestyle changes are crucial for hypertensive heart disease (HHD). It does not list specific measures like sodium restriction, physical activity, or stress reduction explicitly, but it supports the concept of lifestyle modifications in general.

[PMID:31756356] [PARTIAL] Adopting healthy lifestyles, such as being active on >/=4 days per week, weight-loss in the presence of obesity, consuming a diet rich in fruits and vegetables, and sodium below the recommended threshold, avoiding high alcohol consumption and refraining from smoking have been effective lifestyle therapies to prevent or control stage 1 hypertension (HTN). --- Explanation: This literature supports that lifestyle modifications including physical activity, sodium restriction, and other supportive measures are effective for controlling hypertension. However, it does not mention hypertensive heart disease specifically.


MONDO:0005045

[PMID:34533409] [SUPPORT] Hypertrophic cardiomyopathy (HCM) is a complex disease characterized by thickening of the cardiac muscle. Common symptoms include chest pain, shortness of breath, palpitations, fatigue and syncope (fainting), which are often confused for other conditions. --- Explanation: This literature supports the statement as it lists chest pain as a common symptom of Hypertrophic Cardiomyopathy.


MONDO:0005045

[PMID:29655822] [SUPPORT] Heart failure (HF), characterized by excessive exertional dyspnea, is a common complication within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM). --- Explanation: The literature provided mentions that exertional dyspnea is common in patients with hypertrophic cardiomyopathy, supporting the statement that dyspnea is a common phenotype of HCM.


MONDO:0005045

[PMID:29150126] [SUPPORT] Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses. --- Explanation: The excerpt directly states that syncope is a clinical manifestation of hypertrophic cardiomyopathy.

[PMID:36442670] [SUPPORT] Syncope in hypertrophic cardiomyopathy: Explaining the unexplained. --- Explanation: Syncope is highlighted as a phenomenon occurring in individuals with hypertrophic cardiomyopathy.

[PMID:29761339] [SUPPORT] Syncope and presyncope-in addition to extremely variable cardiac symptoms (dyspnea and angina)-are common. --- Explanation: The text explicitly mentions syncope as a common symptom in hypertrophic cardiomyopathy patients.


MONDO:0005045

[PMID:34969871] [SUPPORT] Study aims were to estimate the population-diagnosed prevalence of cardiomyopathies and describe the temporal relationship between a diagnosis of cardiomyopathy with HF and arrhythmia... Between 2010 and 2018, prevalence increased for ARVC by 180% and HCM by 9%. --- Explanation: The study indicates a relationship between hypertrophic cardiomyopathy (HCM) and arrhythmias, supporting the statement that arrhythmias are a common cardiovascular phenotype of HCM.

[PMID:7201843] [SUPPORT] The patients with hypertrophic cardiomyopathy showed a significant increase in supraventricular extrasystoles/24 hours, supraventricular arrhythmias, high grade ventricular arrhythmia, and the number of patients with more than 10 ventricular extrasystoles every 24 hours when compared with the other groups. --- Explanation: This study directly assesses the prevalence and types of arrhythmias in patients with hypertrophic cardiomyopathy, confirming that arrhythmias are a common phenotype.

[PMID:3158692] [SUPPORT] Frequent ventricular premature complexes, complex ventricular ectopic activity and asymptomatic ventricular tachycardia are common to both hypertrophic and dilated cardiomyopathy; in both conditions, sudden death is a common occurrence. --- Explanation: This reference mentions common arrhythmic events in hypertrophic cardiomyopathy, supporting the idea that arrhythmias are a common cardiovascular phenotype in HCM.