MONDO:0018150

[PMID:28218669] [SUPPORT] Loss of bone mass occurs earlier and is more severe in patients with GD and may cause pathological fractures (of long bones, vertebrae, etc.). --- Explanation: Review confirms pathological fractures result from accelerated bone mass loss in Gaucher disease.


MONDO:0018150

[PMID:22010032] [SUPPORT] Erlenmeyer flask deformity is a common radiological finding in patients with Gaucher's disease --- Explanation: Study confirms Erlenmeyer flask deformity is a characteristic radiological finding in Gaucher disease.


MONDO:0018150

[PMID:28218669] [SUPPORT] oculomotor paralysis (or bilateral fixed strabismus) is very suggestive of the disease --- Explanation: Review identifies oculomotor paralysis as part of the diagnostic triad in Type 2.


MONDO:0018150

[PMID:28218669] [SUPPORT] Some patients present moderate systemic involvement with horizontal ophthalmoplegia as the only neurological symptom --- Explanation: Review identifies horizontal ophthalmoplegia as the cardinal and sometimes sole neurological sign in Type 3.


MONDO:0018150

[PMID:28218669] [SUPPORT] Seizures occurring later manifest as myoclonic epilepsy that is resistant to antiepileptic drugs. --- Explanation: Review confirms seizures as a feature of Type 2, progressing to drug-resistant myoclonic epilepsy.


MONDO:0018150

[PMID:28218669] [SUPPORT] others present more severe forms with varying neurological signs including progressive myoclonus epilepsy (16% of patients) --- Explanation: Review documents progressive myoclonus epilepsy in 16% of Type 3 patients.


MONDO:0018150

[PMID:28218669] [SUPPORT] bulbar signs (particularly severe swallowing disorders) --- Explanation: Review identifies severe swallowing disorders (dysphagia) as part of the Type 2 diagnostic triad.


MONDO:0018150

[PMID:28218669] [SUPPORT] hypertonia with pyramidal and possibly extrapyramidal rigidity --- Explanation: Review confirms pyramidal tract involvement with hypertonia and rigidity in Type 2.


MONDO:0018150

[PMID:28218669] [SUPPORT] Psychomotor development is then altered, although some children may still continue to acquire skills. --- Explanation: Review confirms altered psychomotor development as a feature of Type 2.


MONDO:0018150

[PMID:28218669] [SUPPORT] oculomotor paralysis (or bilateral fixed strabismus) is very suggestive of the disease --- Explanation: Review identifies bilateral fixed strabismus as an alternative presentation of oculomotor involvement in Type 2.


MONDO:0018150

[PMID:28218669] [SUPPORT] Growth retardation (30% of patients) may be the first sign, sometimes associated with cachexia. --- Explanation: Review confirms growth retardation in 30% of Type 2 patients, sometimes with cachexia.


MONDO:0018150


MONDO:0018150

[PMID:28218669] [INDIRECT EVIDENCE] [SUPPORT] The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells. --- Explanation: Review confirms Gaucher cell infiltration causes the major clinical manifestations.


MONDO:0018150

[PMID:9497857] [INDIRECT EVIDENCE] [SUPPORT] Severe deficiency of glucocerebrosidase caused by disabling mutations is additionally associated with neurological manifestations that in part reflect a failure to degrade endogenous neuronal glycosphingolipids --- Explanation: Review explains that neuronopathic disease reflects failure to degrade neuronal glycosphingolipids.

[PMID:28218669] [INDIRECT EVIDENCE] [SUPPORT] the accumulation of glucosylsphingosine may cause neuronal dysfunction and death, leading mainly to GD-related neurological symptoms --- Explanation: Review confirms glucosylsphingosine accumulation causes neuronal dysfunction and death.


MONDO:0018150

[PMID:30315684] [INDIRECT EVIDENCE] [SUPPORT] A common feature appears to be microgliosis and subsequent astrogliosis and neuronal loss, particularly in hippocampal regions --- Explanation: Review of postmortem and mouse model studies confirms microgliosis and astrogliosis as common neuropathological features in neuronopathic Gaucher disease.


MAXO:0000933

[PMID:19047232] [SUPPORT] Within 8 years of enzyme replacement therapy, most clinical parameters studied became normal or nearly normal. --- Explanation: Long-term study demonstrates effectiveness of enzyme replacement therapy in children with Gaucher disease.

[PMID:25755533] [SUPPORT] ERT is of no benefit in type 2 disease. --- Explanation: Review confirms ERT does not help neurological disease in Type 2 due to BBB.


MAXO:0020025

[PMID:25688781] [SUPPORT] treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. --- Explanation: Phase 3 ENGAGE trial demonstrates eliglustat substrate reduction therapy effectively improves clinical manifestations in Gaucher disease.


MAXO:0000950


MAXO:0000079


hgnc:4177

[PMID:10464619] [SUPPORT] the presence of a single N370S allele is diagnostic of the type 1 or nonneuronopathic variant --- Explanation: Grabowski review confirms N370S allele is protective against neuronopathic disease.


hgnc:4177

[PMID:10464619] [SUPPORT] the L444P/L444P genotype is highly associated with neuronopathic variants in the Caucasian population --- Explanation: Grabowski review confirms L444P homozygosity predicts neuronopathic disease.


hgnc:4177


hgnc:4177

[PMID:19846850] [SUPPORT] The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. --- Explanation: Landmark multicenter NEJM study confirms strong GBA-Parkinson association with OR 5.43.

[PMID:30315684] [SUPPORT] Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%-20% of idiopathic PD cases depending on ethnicity. --- Explanation: Review confirms GBA mutations are the most significant genetic risk factor for PD.

[PMID:28218669] [SUPPORT] Patients with type-1 GD-but also carriers of GBA1 mutation-have been found to be predisposed to developing Parkinson's disease --- Explanation: Review confirms both GD patients and GBA1 carriers have increased PD risk.


MONDO:0001942

[PMID:39294497] [NO_EVIDENCE] The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. --- Explanation: This snippet supports genetic architecture of anxiety disorders but does not directly evidence the specific clinical phenotype of excessive worry.


MONDO:0001942


MONDO:0001942

[PMID:38865810] [INDIRECT EVIDENCE] [PARTIAL] Evidence indicates that anxiety disorders arise from an imbalance in the functioning of brain circuits that govern the modulation of emotional responses to possibly threatening stimuli. The circuits under consideration in this context include the amygdala's bottom-up activity, which signifies the existence of stimuli that may be seen as dangerous. Moreover, these circuits encompass top-down regulatory processes that originate in the prefrontal cortex, facilitating the communication of the emotional significance associated with the inputs. --- Explanation: This evidence supports the model of amygdala hyperactivity in anxiety and the role of prefrontal cortex in regulating amygdala responses to threat stimuli.


MONDO:0001942

[PMID:38865810] [INDIRECT EVIDENCE] [PARTIAL] A decrease in GABAergic activity is present in both anxiety disorders and severe depression. Research on cerebral functional imaging in depressive individuals has shown reduced levels of GABA within the cortical regions. Additionally, animal studies demonstrated that a reduction in the expression of GABAA/B receptors results in a behavioral pattern resembling anxiety. --- Explanation: This evidence demonstrates reduced GABAergic activity in anxiety disorders through both imaging studies and animal models showing that decreased GABA receptor expression leads to anxiety-like behavior.

[PMID:38865810] [INDIRECT EVIDENCE] [PARTIAL] The amygdala consists of inhibitory networks composed of GABAergic interneurons, responsible for modulating anxiety responses in both normal and pathological conditions. The GABAA receptor has allosteric sites (e.g., α/γ, γ/β, and α/β) which enable regulation of neuronal inhibition in the amygdala. These sites serve as molecular targets for anxiolytic medications such as benzodiazepine and barbiturates. --- Explanation: This supports the mechanism of GABAergic dysfunction in the amygdala and explains how benzodiazepines work by targeting GABAA receptor allosteric sites to enhance inhibition.

[PMID:39294497] [INDIRECT EVIDENCE] [NO_EVIDENCE] We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. --- Explanation: This snippet supports broad genetic architecture of anxiety disorders but does not directly provide evidence for GABA system dysfunction.


MONDO:0001942

[PMID:24936175] [INDIRECT EVIDENCE] [PARTIAL] Decreased serotonergic activity has been implicated in anxiety and major depression, and antidepressants directly or indirectly increase the long-term activity of the serotonin system. A key component of serotonin circuitry is the 5-HT1A autoreceptor, which functions as the major somatodendritic autoreceptor to negatively regulate the 'gain' of the serotonin system. --- Explanation: This evidence establishes the role of decreased serotonergic activity in anxiety and explains how antidepressants work by increasing serotonin system activity.

[PMID:24936175] [INDIRECT EVIDENCE] [PARTIAL] In addition, 5-HT1A heteroreceptors are abundantly expressed post-synaptically in the prefrontal cortex (PFC), amygdala, and hippocampus to mediate serotonin actions on fear, anxiety, stress, and cognition. --- Explanation: This supports the specific role of serotonin signaling in prefrontal-limbic circuits that regulate anxiety and fear responses.


MONDO:0001942

[PMID:20808146] [INDIRECT EVIDENCE] [SUPPORT] Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. --- Explanation: This evidence directly links GAD to HPA axis hyperactivity, particularly in older adults.

[PMID:20808146] [INDIRECT EVIDENCE] [SUPPORT] Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. --- Explanation: This demonstrates that HPA axis hyperactivity with elevated cortisol is present in GAD patients and that successful treatment reduces cortisol levels in parallel with anxiety symptom reduction.


MONDO:0001942

[PMID:37542162] [INDIRECT EVIDENCE] [PARTIAL] Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. --- Explanation: This large-scale epigenome-wide study identifies hundreds of significant DNA methylation sites associated with anxiety disorders, supporting the role of epigenetic mechanisms in GAD pathophysiology.

[PMID:37542162] [INDIRECT EVIDENCE] [PARTIAL] In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. --- Explanation: This identifies FZR1 as a key gene with replicable methylation changes in anxiety, linking epigenetic alterations to hippocampal neurogenesis and fear memory mechanisms.


HGNC.SYMBOL:SLC6A4


HGNC.SYMBOL:COMT


HGNC.SYMBOL:CRHR1


HGNC.SYMBOL:NPY


MONDO:0008538


MONDO:0008538

[PMID:35629030] [INDIRECT EVIDENCE] [SUPPORT] Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), respectively. --- Explanation: This evidence confirms that dendritic cells are key initiators of the immune response in GCA, recruiting and activating CD4 T cells in the vessel wall.


MONDO:0008538

[PMID:35629030] [INDIRECT EVIDENCE] [PARTIAL] IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. --- Explanation: This demonstrates the role of IFN-gamma from Th1 cells in recruiting additional immune cells and promoting macrophage differentiation in the vessel wall.

[PMID:36656970] [INDIRECT EVIDENCE] [PARTIAL] Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1+CD4+ T cells and the functional decline of NOTCH4+ T regulatory cells (Checkpoint 1). --- Explanation: This evidence describes the checkpoint mechanism by which CD4+ T cells become dysregulated through NOTCH signaling, enabling their pathogenic infiltration into the arterial wall.


MONDO:0008538

[PMID:36656970] [INDIRECT EVIDENCE] [SUPPORT] Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). --- Explanation: This describes the immune checkpoint failure that allows multinucleated giant cells to form in the vessel wall through unchecked macrophage activation.

[PMID:35629030] [INDIRECT EVIDENCE] [SUPPORT] Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis. --- Explanation: This evidence explains the mechanism of intimal hyperplasia whereby smooth muscle cells proliferate and produce extracellular matrix, leading to stenosis.


HGNC.SYMBOL:HLA-DRB1*04


MONDO:0001103

[PMID:30020611] [SUPPORT] The clinical presentation typically involves diarrhea, flatulence, abdominal pain, and bloating; however, asymptomatic colonization is also common. --- Explanation: Supports diarrhea as a hallmark frequent phenotype.


MONDO:0001103

[PMID:30020611] [SUPPORT] The clinical presentation typically involves diarrhea, flatulence, abdominal pain, and bloating; however, asymptomatic colonization is also common. --- Explanation: Supports abdominal pain as a common clinical manifestation.

[PMID:17070814] [SUPPORT] Clinical manifestations of Giardia intestinalis infection also vary from asymptomatic carriage to acute and chronic diarrhoea with abdominal pain. --- Explanation: Independent review support for abdominal pain across acute and chronic courses.


MONDO:0001103

[PMID:30020611] [SUPPORT] The clinical presentation typically involves diarrhea, flatulence, abdominal pain, and bloating; however, asymptomatic colonization is also common. --- Explanation: Supports flatulence as a common symptom.


MONDO:0001103

[PMID:30020611] [SUPPORT] The clinical presentation typically involves diarrhea, flatulence, abdominal pain, and bloating; however, asymptomatic colonization is also common. --- Explanation: Supports abdominal bloating/distention as part of the common symptomatic presentation.


MONDO:0001103

[PMID:6750750] [SUPPORT] Giardiasis can produce steatorrhea, maldigestion, and malabsorption of carbohydrates and of vitamins A and B12. --- Explanation: Supports steatorrhea as a recognized malabsorptive manifestation.


MONDO:0001103

[PMID:30020611] [SUPPORT] In some patients, a chronic infection may lead to malabsorption and weight loss. --- Explanation: Supports malabsorption as an important chronic manifestation.

[PMID:35250996] [SUPPORT] Chronic G. duodenalis infections cause a malabsorption syndrome that may lead to failure to thrive and/or stunted growth, especially in children in developing countries. --- Explanation: Provides independent support for chronic malabsorption as a clinically important manifestation.


MONDO:0001103

[PMID:30020611] [SUPPORT] In some patients, a chronic infection may lead to malabsorption and weight loss. --- Explanation: Supports weight loss in persistent/chronic disease.


MONDO:0001103

[PMID:6750750] [SUPPORT] Severe clinical giardiasis can cause "failure to thrive" in young children, but the impact, if any, of subclinical giardiasis on growth in general populations is not well defined. --- Explanation: Supports failure to thrive as a severe pediatric nutritional consequence.

[PMID:35250996] [SUPPORT] Chronic G. duodenalis infections cause a malabsorption syndrome that may lead to failure to thrive and/or stunted growth, especially in children in developing countries. --- Explanation: Adds newer independent support for failure-to-thrive risk in chronic pediatric infection.


MONDO:0001103

[PMID:14501998] [SUPPORT] Further studies of giardiasis in poorly nourished children in developing regions supports an important contributing role of Giardia in stunting and cognitive impairment. --- Explanation: Supports growth delay/stunting as a documented pediatric consequence in vulnerable settings.

[PMID:37764167] [SUPPORT] Structural damages inflicted by both parasites to epithelial cells in the large and small intestines could severely impair children's gut health, including the ability to absorb nutrients, resulting in stunted growth, diminished neurocognitive development, and other long-term effects. --- Explanation: Adds contemporary review support linking intestinal injury and malabsorption to pediatric stunting.


MONDO:0001103

[PMID:14501998] [SUPPORT] Further studies of giardiasis in poorly nourished children in developing regions supports an important contributing role of Giardia in stunting and cognitive impairment. --- Explanation: Supports potential neurodevelopmental sequelae (cognitive impairment) in pediatric chronic exposure contexts.

[PMID:37764167] [SUPPORT] Structural damages inflicted by both parasites to epithelial cells in the large and small intestines could severely impair children's gut health, including the ability to absorb nutrients, resulting in stunted growth, diminished neurocognitive development, and other long-term effects. --- Explanation: Adds independent contemporary support for long-term neurocognitive impact in pediatric disease contexts.


MONDO:0001103

[DOI:10.1136/gutjnl-2023-331835] [SUPPORT] PI-IBS was most associated with parasites (prevalence 30.1%), but in only two studies, followed by bacteria (18.3%) and viruses (10.7%). --- Explanation: Supports parasite-linked post-infectious IBS as a relevant sequela category.

[DOI:10.1136/gutjnl-2023-331835] [SUPPORT] IBS persisted in 39.8% of subjects in the long-term (>5 years follow-up) after diagnosis. --- Explanation: Supports long-term persistence of this sequela once established.


MONDO:0001103

[DOI:10.1136/gutjnl-2023-331835] [SUPPORT] Overall prevalence of PI-IBS and PI-FD were 14.5% and 12.7%, respectively. --- Explanation: Supports post-infectious dyspeptic symptoms (PI-FD) as a recognized long-tail sequela after enteric infection.


MONDO:0001103

[DOI:10.1128/iai.00065-24] [INDIRECT EVIDENCE] [SUPPORT] G. lamblia resides in the lumen and at the epithelial surface of the proximal small intestine but is not mucosa invasive. --- Explanation: Supports non-invasive luminal colonization as a discrete mechanistic stage.


MONDO:0001103

[PMID:22924932] [INDIRECT EVIDENCE] [SUPPORT] All disruptions were caspase-3 dependent and were more pronounced when caused by a non-host specific assemblage. --- Explanation: Supports caspase-3 dependence of trophozoite-induced epithelial apoptosis.


MONDO:0001103


MONDO:0001103

[PMID:22924932] [INDIRECT EVIDENCE] [SUPPORT] The results indicate that infection with trophozoites disrupts epithelial tight junctions and induces varying degrees of enterocyte apoptosis, depending on the infecting assemblage. --- Explanation: Supports trophozoite-induced tight-junction disruption as a specific injury event.


MONDO:0001103

[PMID:35868574] [INDIRECT EVIDENCE] [SUPPORT] Collectively, these results support the emerging theory that molecular oxygen impacts gut homeostasis during Giardia infection via direct host signaling pathways. --- Explanation: Supports oxygen-regulated host-signaling perturbation in infected epithelial cells.


MAXO:0000058

[PMID:15625030] [SUPPORT] Tinidazole is the first-line drug treatment of giardiasis, as it requires only a single dose to cure infection in most individuals. --- Explanation: Supports tinidazole as first-line therapy.

[PMID:15625030] [SUPPORT] The related drug metronidazole is as effective, but it requires 5 to 7 days of three times a day therapy. --- Explanation: Supports metronidazole as an effective alternative regimen.


CHEBI:63627

[PMID:15625030] [INDIRECT EVIDENCE] [SUPPORT] Tinidazole is the first-line drug treatment of giardiasis, as it requires only a single dose to cure infection in most individuals. --- Explanation: Supports tinidazole as first-line therapy.

[PMID:15625030] [INDIRECT EVIDENCE] [SUPPORT] The related drug metronidazole is as effective, but it requires 5 to 7 days of three times a day therapy. --- Explanation: Supports metronidazole as an effective alternative regimen.


CHEBI:6909


MAXO:0000058

[PMID:15625030] [SUPPORT] Nitazoxanide appears in limited studies to be as effective as tinidazole or metronidazole, and it does not have the bitter taste of nitroimidazoles. --- Explanation: Supports nitazoxanide as a reasonable alternative option.

[PMID:18348774] [SUPPORT] Among the 137 children who completed the study (74 given nitazoxanide and 63 given tinidazole), the frequency of parasitological cure following a single dose of tinidazole was significantly higher than that following six doses of nitazoxanide (90.5% v. 78.4%; P<0.05). --- Explanation: Randomized pediatric trial provides comparative efficacy context for nitazoxanide versus tinidazole.


MAXO:0000058

[PMID:15625030] [SUPPORT] A good alternate for use during pregnancy is paromomycin. --- Explanation: Supports paromomycin as a pregnancy-compatible alternative.


CHEBI:7934

[PMID:15625030] [INDIRECT EVIDENCE] [SUPPORT] A good alternate for use during pregnancy is paromomycin. --- Explanation: Supports paromomycin as a pregnancy-compatible alternative.


MAXO:0000058

[DOI:10.1128/aac.00731-23] [SUPPORT] Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of G. lamblia. --- Explanation: Supports active development of alternatives for resistant cases.

[clinicaltrials:NCT02736968] [SUPPORT] This study is designed to compare placebo to once daily doses of 6mg auranofin for adults with amebiasis or giardiasis. --- Explanation: Supports active human trial evaluation of repurposed therapy in giardiasis.


NCBITaxon:5741

[PMID:30020611] [SUPPORT] Giardiasis, caused by the protozoan parasite Giardia duodenalis, is one of the most common treatable causes of gastroenteritis worldwide, with a burden higher in low-income countries. --- Explanation: Supports Giardia duodenalis as the core infectious agent.

[PMID:31630759] [SUPPORT] A total of eight Giardia species are accepted. These include: Giardia duodenalis (syn. Giardia intestinalis and Giardia lamblia), which infects humans and animals, Giardia agilis, Giardia ardeae, Giardia psittaci, Giardia muris, Giardia microti, Giardia peramelis and G. cricetidarum, which infect non-human hosts including amphibians, birds, rodents and marsupials. --- Explanation: Supports that human giardiasis is attributed to G. duodenalis, while other Giardia species are non-human host-adapted.

[PMID:29225147] [SUPPORT] Assemblages display various degree of host specificity, with Assemblages A and B occurring in humans and many other hosts, Assemblage C and D in canids, Assemblage E in hoofed animals, Assemblage F in cats, Assemblage G in rodents, and Assemblage H in pinnipeds. --- Explanation: Clarifies that human infections are concentrated in specific G. duodenalis assemblages rather than distinct non-duodenalis species.


MONDO:0007745

[PMID:7565971] [SUPPORT] People with Gilbert's syndrome have mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis. --- Explanation: Classic description from the landmark NEJM paper establishing unconjugated hyperbilirubinemia as the obligate phenotype.


MONDO:0007745

[PMID:8596320] [SUPPORT] This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice. --- Explanation: Directly establishes jaundice as a clinical presentation of the unconjugated hyperbilirubinaemia in Gilbert's syndrome.

[PMID:8596320] [SUPPORT] Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype. --- Explanation: Demonstrates that homozygous UGT1A1*28 (7/7) carriers have the highest bilirubin levels, making them most susceptible to intermittent jaundice.


MONDO:0007745


MONDO:0007745

[PMID:7565971] [INDIRECT EVIDENCE] [SUPPORT] Hepatic glucuronidating activity, essential for efficient biliary excretion of bilirubin, is reduced to about 30 percent of normal. --- Explanation: The Bosma 1995 NEJM paper demonstrates that UGT1A1 enzyme activity is substantially reduced in Gilbert's syndrome, confirming the enzymatic basis of the condition.

[PMID:7565971] [INDIRECT EVIDENCE] [SUPPORT] These patients were homozygous for two extra bases (TA) in the TATAA element of the 5' promoter region of the gene (A(TA)7TAA rather than the normal A(TA)6TAA). --- Explanation: Identifies the (TA)7 promoter repeat as the molecular basis for reduced UGT1A1 expression in Western populations.

[PMID:9435989] [INDIRECT EVIDENCE] [SUPPORT] Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon. --- Explanation: Clarke 1997 confirms population prevalence (2-19%) and the promoter TA insertion as the principal molecular cause.


MONDO:0007745

[PMID:8596320] [INDIRECT EVIDENCE] [SUPPORT] 14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype. --- Explanation: Demonstrates that fasting precipitates jaundice specifically in homozygous UGT1A1*28 (7/7) carriers, consistent with the fasting-triggering mechanism in Gilbert's syndrome.


MAXO:0000950

[PMID:37390966] [SUPPORT] Gilbert's syndrome, also known as benign hyperbilirubinaemia, was described more than 100 years ago. --- Explanation: The Vitek & Tiribelli 2023 review confirms the longstanding recognition of Gilbert's syndrome as a benign condition, supporting reassurance as the primary therapeutic approach.


MAXO:0000058

[PMID:11990381] [SUPPORT] screening for UGT1A1*28 polymorphism may identify patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan induced gastrointestinal and bone marrow toxicity. --- Explanation: Iyer 2002 prospective pharmacogenetic study demonstrated that UGT1A1*28 genotype predicts reduced SN-38 glucuronidation and severe irinotecan toxicity, establishing the clinical rationale for pre-treatment testing.

[PMID:36443464] [SUPPORT] Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual's starting dose thereby preventing carriers from toxicity. --- Explanation: The DPWG 2023 guideline endorses UGT1A1 variant testing to optimize irinotecan starting dose and prevent severe toxicity.

[PMID:36443464] [SUPPORT] UGT1A1 genotyping is considered "essential", indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment. --- Explanation: DPWG classification of UGT1A1 testing as 'essential' elevates this to a mandatory pre-treatment test, not an optional pharmacogenomics screen.


hgnc:12542

[PMID:7565971] [SUPPORT] Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzyme appears to be necessary for Gilbert's syndrome but not sufficient for the complete manifestation of the syndrome. --- Explanation: Bosma 1995 established the (TA)7 promoter polymorphism as required but not sufficient for full phenotypic expression, explaining incomplete penetrance in heterozygotes.

[PMID:8596320] [SUPPORT] The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%. --- Explanation: Provides population frequency of UGT1A1*28 homozygosity in a Western European population, consistent with Gilbert's syndrome prevalence.

[PMID:9435989] [SUPPORT] Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon. --- Explanation: Clarke 1997 places UGT1A1*28 in the context of the full spectrum of UGT1 defects and confirms its role as the principal cause of Gilbert's syndrome.


hgnc:12542

[PMID:10353933] [SUPPORT] a G-->A transition at nucleotide 211 caused arginine to replace glycine at position 71 of corresponding protein product (G71R). --- Explanation: Maruo 1999 identified the G71R mutation and showed it is associated with hyperbilirubinemia in Japanese neonates, establishing UGT1A1*6 as a relevant variant in East Asian populations.

[PMID:15304120] [SUPPORT] The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations. --- Explanation: Takeuchi 2004 confirmed the ethnic divergence in UGT1A1 variant spectrum, with coding variants like G71R being more prevalent in Japanese patients versus the promoter TA-repeat polymorphism in Caucasians.


MONDO:0005041

[PMID:26497784] [SUPPORT] Apoptosis of retinal ganglion cells (RGCs) in glaucoma causes progressive visual field loss, making it the primary cause of irreversible blindness worldwide. --- Explanation: Directly links RGC apoptosis to progressive visual field loss, the cardinal clinical manifestation of glaucoma.


MONDO:0005041


MONDO:0005041

[PMID:37217093] [SUPPORT] The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. --- Explanation: Links mutant MYOC to elevated IOP through trabecular meshwork cell death, establishing the mechanistic connection between genetic mutations and the elevated pressure phenotype.


MONDO:0005041

[PMID:26497784] [INDIRECT EVIDENCE] [SUPPORT] Elevated intraocular pressure and aging, the main risk factors for glaucoma, accelerate RGC apoptosis. --- Explanation: Identifies elevated IOP as a main risk factor that accelerates retinal ganglion cell apoptosis in glaucoma.


MONDO:0005041

[PMID:26497784] [INDIRECT EVIDENCE] [SUPPORT] Apoptosis of retinal ganglion cells (RGCs) in glaucoma causes progressive visual field loss, making it the primary cause of irreversible blindness worldwide. --- Explanation: Establishes that RGC apoptosis is the direct cause of visual field loss in glaucoma, confirming the central role of programmed cell death in disease pathogenesis.

[PMID:26302410] [INDIRECT EVIDENCE] [SUPPORT] A glaucoma-associated mutant of optineurin, E50K, impairs autophagy as well as vesicle trafficking, leading to death of retinal cells by apoptosis. --- Explanation: Links OPTN mutations to RGC apoptosis through impaired autophagy, providing a molecular mechanism for how genetic variants cause retinal ganglion cell death.

[PMID:37542647] [INDIRECT EVIDENCE] [PARTIAL] Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. --- Explanation: Confirms that RGC death is a hallmark of glaucoma neurodegeneration and highlights the role of neuroinflammation in the degenerative process.


MONDO:0005041

[PMID:10617907] [INDIRECT EVIDENCE] [PARTIAL] Myocilin gene is expressed clearly in the trabecular meshwork cells of both glaucomatous and nonglaucomatous eyes. --- Explanation: Confirms MYOC expression in trabecular meshwork cells, but expression alone only indirectly supports dysfunction.

[PMID:37217093] [INDIRECT EVIDENCE] [SUPPORT] The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. --- Explanation: Describes how mutant myocilin causes trabecular meshwork cell death through intracellular aggregation, directly linking MYOC mutations to trabecular dysfunction and elevated IOP.


MAXO:0000058

[PMID:8942890] [SUPPORT] Purpose: To determine efficacy and safety of latanoprost, a prostaglandin analog for glaucoma, during 1 year of treatment. --- Explanation: This clinical trial directly supports prostaglandin analog therapy, using latanoprost as a representative first-line agent for glaucoma.

[PMID:8942890] [SUPPORT] Conclusion: Latanoprost safely and effectively reduces IOP for 1 year in patients of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma therapy. --- Explanation: This provides direct human evidence that topical latanoprost produces sustained intraocular pressure lowering in glaucoma therapy.


MAXO:0000058

[PMID:16750466] [SUPPORT] Objective: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. --- Explanation: This randomized study directly evaluates topical timolol as an intraocular pressure-lowering treatment in open-angle glaucoma or ocular hypertension.

[PMID:16750466] [SUPPORT] Conclusion: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. --- Explanation: This supports timolol as an effective adjunctive topical beta-blocker therapy for additional pressure reduction.


CHEBI:39465

[PMID:16750466] [INDIRECT EVIDENCE] [SUPPORT] Objective: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. --- Explanation: This randomized study directly evaluates topical timolol as an intraocular pressure-lowering treatment in open-angle glaucoma or ocular hypertension.

[PMID:16750466] [INDIRECT EVIDENCE] [SUPPORT] Conclusion: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. --- Explanation: This supports timolol as an effective adjunctive topical beta-blocker therapy for additional pressure reduction.


MAXO:0000058

[PMID:14660453] [SUPPORT] Methods: 16 newly diagnosed previously untreated glaucoma patients were randomly assigned to either timolol 0.5% or brimonidine 0.2%. --- Explanation: This randomized trial directly supports brimonidine as a therapeutic alpha agonist used in primary open-angle glaucoma.

[PMID:14660453] [SUPPORT] Results: IOP reduction was similar for both groups (p<0.05). --- Explanation: This supports clinically meaningful intraocular pressure lowering with brimonidine in glaucoma treatment.


CHEBI:3175

[PMID:14660453] [INDIRECT EVIDENCE] [SUPPORT] Methods: 16 newly diagnosed previously untreated glaucoma patients were randomly assigned to either timolol 0.5% or brimonidine 0.2%. --- Explanation: This randomized trial directly supports brimonidine as a therapeutic alpha agonist used in primary open-angle glaucoma.

[PMID:14660453] [INDIRECT EVIDENCE] [SUPPORT] Results: IOP reduction was similar for both groups (p<0.05). --- Explanation: This supports clinically meaningful intraocular pressure lowering with brimonidine in glaucoma treatment.


MAXO:0000058

[PMID:16750466] [SUPPORT] Objective: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. --- Explanation: This randomized study directly evaluates brinzolamide, a topical carbonic anhydrase inhibitor, as an IOP-lowering therapy in glaucoma or ocular hypertension.

[PMID:16750466] [SUPPORT] Conclusion: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. --- Explanation: This supports topical carbonic anhydrase inhibition, represented here by brinzolamide, as an effective adjunctive strategy for lowering intraocular pressure.


CHEBI:4702

[PMID:16750466] [INDIRECT EVIDENCE] [SUPPORT] Objective: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. --- Explanation: This randomized study directly evaluates brinzolamide, a topical carbonic anhydrase inhibitor, as an IOP-lowering therapy in glaucoma or ocular hypertension.

[PMID:16750466] [INDIRECT EVIDENCE] [SUPPORT] Conclusion: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. --- Explanation: This supports topical carbonic anhydrase inhibition, represented here by brinzolamide, as an effective adjunctive strategy for lowering intraocular pressure.


CHEBI:3176


MAXO:0000058

[PMID:29199013] [SUPPORT] Purpose: To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension. --- Explanation: This phase 3 clinical program directly supports rho kinase inhibitor therapy using netarsudil in open-angle glaucoma or ocular hypertension.

[PMID:29199013] [SUPPORT] Conclusions: In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. --- Explanation: This supports netarsudil-based rho kinase inhibition as an effective and tolerated topical treatment option.


MAXO:0001082

[PMID:33980505] [SUPPORT] Interventions: Mitomycin C augmented trabeculectomy (n=227) and escalating medical management with intraocular pressure reducing drops (n=226) --- Explanation: This randomized trial directly evaluates trabeculectomy as a primary interventional treatment for advanced open-angle glaucoma.

[PMID:33980505] [SUPPORT] Conclusion: Primary trabeculectomy had similar quality of life and safety outcomes and achieved a lower intraocular pressure compared with primary medication. --- Explanation: This supports trabeculectomy as a clinically effective pressure-lowering option in advanced glaucoma.


HGNC.SYMBOL:MYOC

[PMID:37217093] [SUPPORT] Mutations in the gene MYOC account for approximately 5% of cases of primary open angle glaucoma (POAG). --- Explanation: Establishes MYOC as a causative gene for POAG, accounting for a significant proportion of cases.

[PMID:37217093] [SUPPORT] While myocilin is expressed in numerous tissues, mutant myocilin is only associated with disease in the anterior segment of the eye, in the trabecular meshwork. --- Explanation: Demonstrates tissue-specific pathogenicity of MYOC mutations in the trabecular meshwork of the eye.


HGNC.SYMBOL:OPTN

[PMID:26302410] [SUPPORT] Certain mutations in optineurin (gene OPTN) are associated with primary open angle glaucoma. --- Explanation: Confirms OPTN mutations as a genetic risk factor for primary open angle glaucoma.

[PMID:26302410] [SUPPORT] Thus, an optimum level of optineurin-mediated autophagy is crucial for survival of retinal cells, and impaired autophagy is likely to contribute to glaucoma pathogenesis. --- Explanation: Explains how OPTN variants contribute to glaucoma through dysregulated autophagy in retinal cells.


HGNC.SYMBOL:WDR36


HGNC.SYMBOL:CAV1/CAV2


MONDO:0850335


MAXO:0000004


MAXO:0000014


MAXO:0000647


NCIT:C1244


MAXO:0000944


MAXO:0000058


NCIT:C2039


HGNC.SYMBOL:TERT

[PMID:30333046] [SUPPORT] TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). --- Explanation: Abstract reports TERT promoter mutations in the majority of IDH-wildtype glioblastomas.


HGNC.SYMBOL:EGFR


HGNC.SYMBOL:PTEN


HGNC.SYMBOL:CDKN2A/CDKN2B


HGNC.SYMBOL:TP53


HGNC.SYMBOL:NF1


MONDO:0850335

[PMID:17974913] [SUPPORT] Malignant astrocytic gliomas such as glioblastoma are the most common and lethal --- Explanation: Abstract groups glioblastoma among malignant astrocytic gliomas.


MONDO:0005775

[PMID:17611006] [SUPPORT] People, usually males, with deficient alleles are susceptible to neonatal jaundice, and acute hemolytic anemia, usually during infection, after treatment with certain drugs or after eating fava beans. --- Explanation: The text supports that G6PD deficiency is associated with hemolytic anemia, jaundice, and other hematologic phenotypes.

[PMID:32600868] [SUPPORT] Although most individuals are asymptomatic, exposure to certain food, drugs, or infections can trigger acute hemolytic anemia. --- Explanation: The mention of hemolytic anemia as a potential trigger due to G6PD deficiency supports the statement.

[PMID:35465846] [SUPPORT] The characteristic of glucose-6-phosphate dehydrogenase (G6PD) deficiency is red blood cell (RBC) destruction in response to oxidative stress. --- Explanation: This supports the hematologic nature of the phenotypes associated with G6PD deficiency.

[PMID:27974910] [NO_EVIDENCE] G6PD deficiency is a risk factor of neonatal sepsis and also a justification for more male involvement in this disease. --- Explanation: The reference highlights the role of G6PD deficiency in neonatal sepsis, supporting the association with hematologic issues.

[PMID:28982343] [SUPPORT] The highest prevalence of hemolytic crisis in G6PD deficiency patients was found within the age group of 1-3 years. --- Explanation: The study confirms that hemolytic anemia is a common phenotype in G6PD deficiency.

[PMID:30161219] [NO_EVIDENCE] A moderate decrease in G6PD activity is associated with PAH. --- Explanation: The reference supports the hematologic impact of G6PD deficiency.


MONDO:0005775

[PMID:19589177] [SUPPORT] In Vietnam the blackwater fever syndrome (BWF) has been associated with malaria infection, quinine ingestion and G6PD deficiency. --- Explanation: Blackwater fever syndrome (BWF) characterized by dark urine is associated with G6PD deficiency, supporting the statement that dark urine occurs during acute hemolytic episodes, which fits the genitourinary category.

[PMID:4556779] [PARTIAL] Hemolysis in glucose-6-phosphate dehydrogenase deficiency. --- Explanation: Although the reference does not explicitly mention dark urine, it implies hemolysis during acute episodes which is known to cause dark urine as a result of hemoglobinuria, indirectly supporting the statement.


MONDO:0005775

[PMID:508636] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) deficiency was detected in 16 (69.6%) of a group of 23 neonates who had unexplained moderate or severe jaundice. --- Explanation: This study shows a high incidence of moderate or severe jaundice in G6PD-deficient neonates, supporting the claim that neonatal jaundice is a common systemic phenotype in these individuals and may be severe.

[PMID:27040960] [SUPPORT] G6PD-deficient persons are mostly asymptomatic, but they can develop severe jaundice during the neonatal period. --- Explanation: The literature states that severe neonatal jaundice is associated with G6PD deficiency, supporting the statement's note about the potential severity.

[PMID:19233695] [SUPPORT] This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia. --- Explanation: The study confirms that G6PD deficiency causes neonatal hyperbilirubinemia (jaundice), reinforcing the statement.

[PMID:17611006] [SUPPORT] People, usually males, with deficient alleles are susceptible to neonatal jaundice, and acute hemolytic anemia, usually during infection, after treatment with certain drugs or after eating fava beans. --- Explanation: This reference supports the statement by confirming susceptibility to neonatal jaundice in G6PD-deficient individuals.


MONDO:0005775

[PMID:31235029] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an erythrocyte enzyme defect that amplifies the susceptibility of erythrocytes to oxidative stress due to excessive levels of reactive oxygen species. Consequently, erythrocyte destruction and hemolysis occur. --- Explanation: Hemolysis from G6PD deficiency leads to anemia, which manifests as pallor due to decreased red blood cell count.


MONDO:0005775


MONDO:0005775

[PMID:27040960] [INDIRECT EVIDENCE] [SUPPORT] G6PD deficiency, one of the commonest inherited enzyme abnormalities in humans, arises through one of many possible mutations, most of which reduce the stability of the enzyme and its level as red cells age. --- Explanation: The snippet confirms that mutations in the G6PD gene lead to reduced enzyme activity.

[PMID:1580603] [INDIRECT EVIDENCE] [PARTIAL] Most of the studies have been performed in glucose-6-phosphate dehydrogenase deficiency, where a large number of point mutations have been identified. --- Explanation: The excerpt indicates that mutations are identified in G6PD deficiency, implying a link to decreased enzyme activity.

[PMID:30279493] [INDIRECT EVIDENCE] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations. --- Explanation: The snippet clearly states that G6PD deficiency is caused by numerous point mutations.

[PMID:33051526] [INDIRECT EVIDENCE] [PARTIAL] The results showed that the overall prevalence of G6PD deficiency in China was 2.10% at the national level. The top six common mutations were c.1388 G>A, c.1376 G>T, c.95 A>G, c.392 G>T, c.871 G>A and c.1024 C>T, accounting for more than 90% of G6PD deficient alleles. --- Explanation: This identifies specific mutations that lead to G6PD deficiency and thus, decreased enzyme activity.

[PMID:23275194] [INDIRECT EVIDENCE] [SUPPORT] G6PD gene mutations cause deficiency of the enzyme and a large spectrum of diseases. --- Explanation: Specifically notes that G6PD gene mutations lead to enzyme deficiency.

[PMID:34138756] [INDIRECT EVIDENCE] [NO_EVIDENCE] Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (approximately 5%). --- Explanation: This reference discusses the prevalence of G6PD deficiency, indirectly supporting the statement by establishing the link between mutations and enzyme deficiency.

[PMID:30161219] [INDIRECT EVIDENCE] [NO_EVIDENCE] As G6PD deficiency was previously reported in a limited number of PAH cases, we tested whether iPAH patients exhibit underlying G6PD alterations in erythrocytes --- Explanation: While the primary focus is on PAH, this underscores that decreased G6PD activity results from genetic mutations.


MONDO:0005775

[PMID:7602782] [INDIRECT EVIDENCE] [SUPPORT] Glucose 6-phosphate dehydrogenase (G6PD) plays a key role in the generation of NADPH which is essential for maintaining glutathione in the reduce state, and in the production of ribose 5-phosphate for the synthesis of nucleotides --- Explanation: This reference states that G6PD is crucial for generating NADPH, which is essential for maintaining cellular redox balance.

[PMID:31500396] [INDIRECT EVIDENCE] [SUPPORT] The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. --- Explanation: This reference confirms that adequate G6PD activity is critical for maintaining redox homeostasis by generating NADPH.

[PMID:35880537] [INDIRECT EVIDENCE] [SUPPORT] However, ROS are regulated by a key enzyme called G6PD via the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which controls the generation and removal of ROS in a tissue-specific manner. --- Explanation: This reference indicates that G6PD plays a crucial role in regulating ROS via NADPH production, thus confirming the role of G6PD in maintaining redox balance.

[PMID:20484601] [INDIRECT EVIDENCE] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) is an important site of metabolic control in the pentose phosphate pathway (PPP), providing reducing power (NADPH) and pentose phosphates. --- Explanation: This reference states that G6PD controls metabolic processes in the pentose phosphate pathway, providing NADPH necessary for redox balance.


MONDO:0005775

[PMID:17623517] [INDIRECT EVIDENCE] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is indispensable to maintenance of the cytosolic pool of NADPH and thus the cellular redox balance. --- Explanation: The literature confirms that G6PD deficiency disrupts NADPH levels, impairing the cell's ability to handle oxidative stress, which is consistent with the statement.

[PMID:31961822] [INDIRECT EVIDENCE] [SUPPORT] Fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. --- Explanation: The study describes how G6PD deficiency leads to impaired management of oxidative stress in red blood cells due to defects in glutathione homeostasis, supporting the statement.

[PMID:19769422] [INDIRECT EVIDENCE] [SUPPORT] Numerous drugs, infections, and metabolic conditions have been shown to cause acute hemolysis of red blood cells in the G6PD-deficient patient... The most effective management strategy is to prevent hemolysis by avoiding oxidative stressors. --- Explanation: This reference supports the idea that decreased NADPH levels in G6PD deficiency impair the ability of red blood cells to handle oxidative stress, leading to hemolysis.

[PMID:31235029] [INDIRECT EVIDENCE] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an erythrocyte enzyme defect that amplifies the susceptibility of erythrocytes to oxidative stress... Consequently, erythrocyte destruction and hemolysis occur. --- Explanation: This article confirms that G6PD deficiency amplifies susceptibility to oxidative stress in erythrocytes, leading to hemolysis.

[PMID:11763298] [INDIRECT EVIDENCE] [PARTIAL] G6PD generates nicotinamide adenine dinucleotide phosphate (NADPH), a co-factor in the synthesis of nitric oxide... Currently, there are 200 million people worldwide with red cell x-linked chromosome defects who... are at greater risk of developing hypertension or diabetes mellitus than those racial groups without the defect. --- Explanation: Although this study mainly discusses other health outcomes, it acknowledges the role of G6PD in generating NADPH, thus supporting the connection to oxidative stress and hemolysis due to deficiency.


MONDO:0005775

[PMID:31609781] [INDIRECT EVIDENCE] [SUPPORT] The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods. --- Explanation: This reference clearly states that G6PD deficiency can lead to hemolysis when exposed to oxidative stressors like infections, certain medications, and foods.

[PMID:32600868] [INDIRECT EVIDENCE] [SUPPORT] Although most individuals are asymptomatic, exposure to certain food, drugs, or infections can trigger acute hemolytic anemia. --- Explanation: The abstract supports the statement by mentioning that G6PD deficiency can trigger acute hemolytic anemia when exposed to specific oxidative stressors.

[PMID:31235029] [INDIRECT EVIDENCE] [SUPPORT] The possible mechanism of oxidative stress-mediated destruction of erythrocytes in G6PD deficient individuals induced by periodontal infection is highlighted. --- Explanation: This reference discusses the mechanism of oxidative stress-mediated hemolysis in individuals with G6PD deficiency, supporting the statement.

[PMID:33313989] [INDIRECT EVIDENCE] [SUPPORT] Ingestion of fava beans, as well as infection and certain drugs, are the most typical causes of acute hemolysis in people with G6PD deficiency. --- Explanation: The reference explicitly mentions that certain foods (like fava beans), infections, and drugs can cause acute hemolysis in G6PD-deficient individuals.

[PMID:30380124] [INDIRECT EVIDENCE] [SUPPORT] Although the resulting hemolysis is most often associated with drug exposure, it has also been reported after consumption of certain foods. --- Explanation: The reference confirms that hemolysis in G6PD deficiency can be triggered by certain foods and medications.


MAXO:0001014

[PMID:31609781] [SUPPORT] By recognizing the potential for G6PD deficiency, clinicians can screen for the disorder and teach affected patients how to avoid triggers that result in harmful clinical manifestations. --- Explanation: The statement is supported by the reference as it mentions the importance of avoiding triggers that can lead to harmful clinical manifestations in individuals with G6PD deficiency.

[PMID:32600868] [SUPPORT] Although most individuals are asymptomatic, exposure to certain food, drugs, or infections can trigger acute hemolytic anemia. Given the potential for coronavirus to trigger oxidative stress, unrecognized G6PD deficiency in the presence of the COVID-19 viral infection may cause hemolytic crisis and worse outcome in affected individuals. --- Explanation: The reference supports the statement by highlighting the importance of avoiding oxidative stressors to prevent acute hemolytic anemia in G6PD-deficient individuals.

[PMID:31235029] [SUPPORT] The possible mechanism of oxidative stress-mediated destruction of erythrocytes in G6PD deficient individuals induced by periodontal infection is highlighted. --- Explanation: This reference supports the statement by discussing the increased risk of oxidative stress-mediated destruction of erythrocytes, indicating the importance of avoiding such stressors.

[PMID:31089417] [SUPPORT] G6PD deficiency, theoretically, renders red blood cells (RBC) susceptible to oxidative stress. --- Explanation: The reference supports the statement by emphasizing the susceptibility of G6PD-deficient individuals to oxidative stress and the potential benefits of avoiding such stressors.


MAXO:0000756

[PMID:34105166] [SUPPORT] 33% of patients had Hb < 50 g/L and were all transfused. 50% had Hb between 50 and 65 g/L, half of them (n = 49) did not receive transfusion and only two patients (4%) required transfusion upon follow up. A restrictive transfusion strategy was adopted... --- Explanation: This study indicates that during acute hemolytic crisis in G6PD-deficient children, blood transfusions were given to those with severe anemia, supporting the necessity of blood transfusion for severe cases.

[PMID:16225031] [SUPPORT] Because acute hemolysis is caused by exposure to an oxidative stressor in the form of an infection, oxidative drug, or fava beans, treatment is geared toward avoidance of these and other stressors. Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a blood transfusion. --- Explanation: The statement that management involves hydration, blood transfusions when necessary, and monitoring for complications aligns with the literature, which suggests blood transfusion in severe cases and the self-limited nature of acute hemolysis.

[PMID:34383774] [SUPPORT] G6PD-deficient individuals are susceptible to hemolysis during oxidative stress, which can occur from exposure to certain medications, including 8-aminoquinolines used to treat Plasmodium vivax malaria. Accordingly, access to point-of-care (POC) G6PD testing in Brazil is critical for safe treatment... --- Explanation: The context of oxidative stress and acute hemolysis in G6PD-deficient individuals points towards the requirement for careful monitoring and supportive care to mitigate severe outcomes.

[PMID:23815264] [SUPPORT] Patients requiring RBC transfusions may simultaneously receive oxidative medications or have concurrent infections, both of which can induce haemolysis in G6PD-deficient RBCs...discusses G6PD deficiency, its importance in transfusion medicine... --- Explanation: This reference discusses the role of transfusions and monitoring in the management of hemolysis in G6PD-deficient patients during oxidative stress events.


HGNC.SYMBOL:G6PD

[PMID:32702756] [SUPPORT] Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD. --- Explanation: The snippet indicates that G6PD deficiency is caused by mutations in the X-linked gene G6PD, which aligns with the statement about the genetic inheritance being X-linked recessive.

[PMID:33560519] [SUPPORT] Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder. --- Explanation: The snippet explicitly mentions that G6PD deficiency is an X-linked recessive disorder.

[PMID:24460025] [SUPPORT] Glucose-6-Phosphate Dehydrogenase (G6PD) gene is located at the X-chromosome at Xq28 and the disease is recessively inherited predominantly in males. --- Explanation: This reference specifies the location of the G6PD gene on the X-chromosome and indicates that the disorder is inherited in a recessive manner.


ECTO:0000231

[PMID:31609781] [SUPPORT] The G6PD enzyme is critical to protecting erythrocytes against oxidative stress, and deficiency may lead to hemolysis in the presence of certain environmental factors such as infection and some medications and foods. --- Explanation: The literature explicitly mentions that environmental factors, including infection, medications, and foods, can lead to hemolysis in patients with G6PD deficiency.

[PMID:24372186] [SUPPORT] primaquine and other drugs can trigger acute haemolytic anaemia in subjects who have an inherited mutation of the glucose 6-phosphate dehydrogenase (G6PD) gene. --- Explanation: This reference supports the statement by mentioning that medications like primaquine are known to trigger hemolytic anemia in G6PD deficient individuals.

[PMID:30380124] [SUPPORT] fava beans can provoke severe oxidative hemolysis in individuals with G6PD deficiency. --- Explanation: This reference mentions that consumption of fava beans can provoke hemolysis, supporting the statement regarding foods as triggering factors.

[PMID:32600868] [SUPPORT] exposure to certain food, drugs, or infections can trigger acute hemolytic anemia. --- Explanation: The literature clearly states that food, drugs, and infections can act as triggers for hemolytic anemia in individuals with G6PD deficiency.

[PMID:27081765] [SUPPORT] it is known that a number of drugs, foods and chemicals can trigger haemolysis in G6PD deficient individuals. --- Explanation: This reference supports the statement by indicating that various environmental factors, including drugs and foods, can trigger hemolysis in G6PD-deficient individuals.

[PMID:9827875] [SUPPORT] Five cases of hemolytic episodes arising from the loading of trinitrotoluene (TNT) were detected. ... All five workers showed absolute G6PD deficiency. --- Explanation: The incidence of hemolytic episodes in the context of TNT exposure further supports that environmental factors can trigger hemolysis in G6PD-deficient individuals.


MONDO:0009281

[PMID:39185018] [SUPPORT] The most common clinical manifestations included increased head circumference (77.19%) --- Explanation: Literature review of Chinese GA1 patients shows macrocephaly in 77% of cases.


MONDO:0009281

[PMID:37474264] [SUPPORT] The diffusional kurtosis imaging metrics of the temporal lobe and basal ganglia were significantly correlated with the Barry-Albright dystonia scores. --- Explanation: DKI imaging demonstrates that basal ganglia microstructural changes correlate with dystonia severity scores.


MONDO:0009281

[PMID:39185018] [SUPPORT] motor developmental delay (65.15%) --- Explanation: Literature review shows motor delay in 65% of GA1 patients.


MONDO:0009281

[PMID:35639256] [SUPPORT] commonly manifest acute encephalopathy associated with severe striatum degeneration --- Explanation: Acute encephalopathy with striatal degeneration is the hallmark neurological event.


MONDO:0009281

[PMID:26219480] [SUPPORT] Children with GA1 are reported to be predisposed to subdural hematoma (SDH) development due to stretching of cortical veins secondary to cerebral atrophy and expansion of CSF spaces. --- Explanation: Systematic review establishing the predisposition to SDH in GA1 and the need to distinguish from abusive head trauma.

[PMID:26219480] [SUPPORT] SDHs in 19/20 children with GA1 are accompanied by other brain abnormalities specific for GA1. --- Explanation: SDHs in GA1 almost always co-occur with other GA1-specific brain abnormalities, distinguishing them from abusive head trauma.


MONDO:0009281


MONDO:0009281

[PMID:34588557] [PARTIAL] The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. --- Explanation: Cognitive impairment is documented, particularly in high excreters, but median IQ of 87 is below-average rather than meeting the threshold for intellectual disability (IQ <70). Most NBS-identified patients have mild cognitive effects rather than frank intellectual disability.


MONDO:0009281

[PMID:26219480] [SUPPORT] cerebral atrophy and expansion of CSF spaces --- Explanation: Cerebral atrophy with CSF space expansion is a recognized GA1 neuroimaging feature.


MONDO:0009281

[PMID:37474264] [SUPPORT] Diffusional kurtosis imaging provides more comprehensive quantitative information regarding the gray and white matter micropathologic damage in glutaric aciduria type 1 than routine MR imaging scores. --- Explanation: Supports white matter microstructural injury in GA1, consistent with MRI white matter abnormalities.


MONDO:0009281

[PMID:37685964] [INDIRECT EVIDENCE] [SUPPORT] An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. --- Explanation: Comprehensive biochemical characterization of GCDH misfolding across multiple variants.

[PMID:37685964] [INDIRECT EVIDENCE] [SUPPORT] The reduced cellular activity was associated with loss of tetramerization. --- Explanation: Loss of the native tetrameric assembly directly impairs enzymatic activity.

[PMID:37685964] [INDIRECT EVIDENCE] [SUPPORT] The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. --- Explanation: Establishes GA1 as a protein misfolding disorder, opening avenues for pharmacological chaperone therapy.


MONDO:0009281

[PMID:37075130] [INDIRECT EVIDENCE] [SUPPORT] Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. --- Explanation: Defines GA1 as GCDH deficiency at the terminal step of lysine catabolism.

[PMID:37685964] [INDIRECT EVIDENCE] [SUPPORT] Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. --- Explanation: Supports the core enzymatic deficiency in GA1.


MONDO:0009281

[PMID:38983872] [INDIRECT EVIDENCE] [SUPPORT] a lack of treatment on an HLD triggers very high accumulation of glutaric acid, 3-hydroxyglutaric acid, and glutarylcarnitine in tissues, with about 60% death due to brain accumulation of toxic lysine metabolites. --- Explanation: Supports toxic metabolite accumulation in brain as a proximal injury step.

[PMID:37075130] [INDIRECT EVIDENCE] [SUPPORT] the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches --- Explanation: Rescue by liver-directed interventions supports metabolite burden as a causal brain-injury mediator.


MONDO:0009281

[PMID:35639256] [INDIRECT EVIDENCE] [SUPPORT] Increased lipid peroxidation and altered antioxidant defenses, including decreased concentrations of reduced glutathione and increased activities of superoxide dismutase, catalase, and glutathione transferase, were observed in the striatum and cerebral cortex of Gcdh-/- mice. --- Explanation: Demonstrates oxidative stress in striatum and cortex of GCDH-deficient mice.

[PMID:35639256] [INDIRECT EVIDENCE] [SUPPORT] the nuclear content of NF-κB was increased, and the cytosolic content of IκBα decreased in the striatum of the mutant animals, indicating a pro-inflammatory response. --- Explanation: Shows NF-kB-mediated neuroinflammation in the striatum.


MONDO:0009281

[PMID:35639256] [INDIRECT EVIDENCE] [SUPPORT] commonly manifest acute encephalopathy associated with severe striatum degeneration and progressive cortical and striatal injury --- Explanation: Confirms striatal degeneration as a hallmark of GA1 neuropathology.

[PMID:37474264] [INDIRECT EVIDENCE] [SUPPORT] The mean kurtosis values of the anterior and posterior putamen and Barry-Albright dystonia scores were most relevant (r = 0.721, 0.730, respectively). --- Explanation: DKI imaging demonstrates that putamen microstructural damage correlates with dystonia severity.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [INDIRECT EVIDENCE] [SUPPORT] crises result in acute bilateral striatal injury and subsequent complex movement disorders. --- Explanation: GeneReviews summarizes the canonical striatal injury to movement-disorder progression in untreated GA1.


MAXO:0000088

[PMID:34588557] [PARTIAL] Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. --- Explanation: Diet is standard of care but current therapy does not fully prevent cognitive impairment, particularly in high excreters.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] Combined metabolic therapy includes low-lysine diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts. --- Explanation: GeneReviews supports low-lysine diet as a core component of combined metabolic therapy aimed at reducing neurotoxic exposure.


MAXO:0000058

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] Combined metabolic therapy includes low-lysine diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts. --- Explanation: GeneReviews identifies carnitine supplementation as part of standard combined metabolic treatment in GA1.


CHEBI:17126

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [INDIRECT EVIDENCE] [SUPPORT] Combined metabolic therapy includes low-lysine diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts. --- Explanation: GeneReviews identifies carnitine supplementation as part of standard combined metabolic treatment in GA1.


MAXO:0000950

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] Combined metabolic therapy includes low-lysine diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts. --- Explanation: GeneReviews supports emergency treatment during illness/stress as a core preventive strategy to reduce CNS toxic exposure.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] <i>Agents/circumstances to avoid:</i> Excessive dietary protein or protein malnutrition inducing catabolic state, prolonged fasting, catabolic illness (intercurrent infection; brief febrile illness post vaccination), inadequate caloric provision during other stressors (e.g., surgery or procedure requiring fasting/anesthesia). --- Explanation: Defines key catabolic triggers that emergency protocols are designed to prevent or mitigate.


MAXO:0000124

[PMID:39728403] [SUPPORT] the proposed digital-tier strategy based on logistic regression analysis, ridge regression, and support vector machine reduced the false-positive rate by over 90% compared to regular NBS while identifying all confirmed individuals with GA1 correctly. --- Explanation: Machine learning approaches can dramatically improve NBS specificity for GA1.

[PMID:39185018] [SUPPORT] 38.36% were diagnosed through newborn screening --- Explanation: NBS is an important diagnostic route for GA1 in China.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] Because the early initiation of treatment dramatically improved the outcome for persons with GA-1, an international guideline group has recommended NBS. --- Explanation: GeneReviews directly supports NBS as outcome-improving and guideline-recommended in GA1.


MAXO:0000079

[PMID:39185018] [SUPPORT] These findings facilitate the diagnosis and treatment of affected children and provide a basis for genetic counseling and prenatal diagnosis for their families. --- Explanation: Genetic variant identification enables genetic counseling and prenatal diagnosis.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] <i>Evaluation of relatives at risk:</i> Testing of all at-risk sibs of any age to allow for early diagnosis and treatment. --- Explanation: GeneReviews supports proactive testing of at-risk siblings as part of counseling and preventive care.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] Once the <i>GCDH</i> pathogenic variants in an affected family member are known, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. --- Explanation: Confirms scope of reproductive and familial counseling options once familial variants are identified.


MAXO:0001001

[PMID:37075130] [SUPPORT] the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective Gcdh gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase (Aass) gene. --- Explanation: Preclinical evidence for two liver-directed gene therapy strategies for GA1.

[PMID:38983872] [SUPPORT] Neonatal treatment with AAV-GCDH restores GCDH expression and enzyme activity in liver and striatum. --- Explanation: Systemic AAV9-GCDH delivery restores enzyme activity in target tissues.

[PMID:38983872] [SUPPORT] AAV-GCDH significantly ameliorates the striatal neuropathology, minimizing neuronal dysfunction, gliosis, and alterations in myelination. --- Explanation: Gene therapy prevents striatal neuropathology in the GA1 mouse model.


MAXO:0000058

[PMID:35639256] [SUPPORT] in vivo treatment with the pan-PPAR agonist bezafibrate normalized these alterations. --- Explanation: Bezafibrate treatment normalized oxidative stress and inflammatory markers in GCDH-deficient mice.

[PMID:35639256] [SUPPORT] bezafibrate should be tested as a potential adjuvant therapy for GA1. --- Explanation: Authors propose bezafibrate as a potential adjuvant therapy based on preclinical evidence.


CHEBI:47612

[PMID:35639256] [INDIRECT EVIDENCE] [SUPPORT] in vivo treatment with the pan-PPAR agonist bezafibrate normalized these alterations. --- Explanation: Bezafibrate treatment normalized oxidative stress and inflammatory markers in GCDH-deficient mice.

[PMID:35639256] [INDIRECT EVIDENCE] [SUPPORT] bezafibrate should be tested as a potential adjuvant therapy for GA1. --- Explanation: Authors propose bezafibrate as a potential adjuvant therapy based on preclinical evidence.


hgnc:4189

[PMID:39185018] [SUPPORT] 67 distinct GCDH gene variants were identified among 73 patients, with missense variants being the most prevalent type (73.97%). The most frequent variant was c.1244-2 A > C, observed in 17.12% of cases. --- Explanation: Comprehensive literature review of GCDH variant spectrum in Chinese GA1 patients.

[PMID:37685964] [SUPPORT] The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. --- Explanation: Demonstrates that missense variants cause protein misfolding affecting biochemical phenotype.

[PMID:39185018] [SUPPORT] the majority of variant sites were located in exons 11 (25.37%) and 6 (22.39%). --- Explanation: Identifies mutational hotspots in the GCDH gene.


MONDO:0009281

[PMID:39185018] [SUPPORT] Sequencing results showed each case had compound heterozygous variants in GCDH(NM_000159.4) --- Explanation: Demonstrates compound heterozygous inheritance pattern consistent with autosomal recessive transmission.

[url:https://www.ncbi.nlm.nih.gov/books/NBK546575/?report=printable] [SUPPORT] At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. --- Explanation: GeneReviews provides the canonical 25/50/25 autosomal recessive recurrence risk framework for GA1 families.


MONDO:0002413

[PMID:20301489] [SUPPORT] Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. --- Explanation: GeneReviews describes hepatomegaly as a defining feature of GSD I.


MONDO:0002413

[PMID:20301489] [SUPPORT] Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. More commonly, untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews confirms fasting hypoglycemia as a cardinal feature of GSD I.


MONDO:0002413

[PMID:20301489] [SUPPORT] untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews confirms lactic acidosis as a presenting feature of untreated GSD I.


MONDO:0002413

[PMID:20301489] [SUPPORT] untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews confirms hypertriglyceridemia as a presenting feature.


MONDO:0002413

[PMID:20301489] [SUPPORT] untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews confirms hyperuricemia as a presenting feature.


MONDO:0002413

[PMID:20301489] [SUPPORT] Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. --- Explanation: GeneReviews confirms nephromegaly due to glycogen and fat accumulation.


MONDO:0002413

[PMID:20301489] [SUPPORT] Affected children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen. --- Explanation: GeneReviews describes short stature as a typical feature.

[PMID:12373568] [SUPPORT] Mean height standard deviation score (SDS) was -1.2+/-1.3, significantly less than the mean target height of -0.2+/-1.1 ( P<0.01). --- Explanation: Long-term cornstarch study demonstrates persistent short stature even with treatment.


MONDO:0002413

[PMID:12373570] [SUPPORT] Hepatic adenomas occur in 22%-75% of affected adults, according to the population studied, and from those reported in the literature are thought to have an approximately 10% risk of undergoing malignant transformation. --- Explanation: Review confirms high frequency of hepatic adenomas in GSD I adults with malignant potential.

[PMID:12373568] [SUPPORT] Of all subjects, 50% had at least one focal hepatic lesion consistent with an adenoma. --- Explanation: Long-term outcome study found adenomas in 50% of subjects despite cornstarch therapy.


MONDO:0002413

[PMID:20301489] [SUPPORT] untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews confirms hyperlipidemia as a presenting feature.


MONDO:0002413

[PMID:20301489] [SUPPORT] Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. --- Explanation: GeneReviews describes epistaxis as a consequence of bleeding diathesis in GSD I.


MONDO:0002413

[PMID:19741523] [SUPPORT] Glycogen storage disease type Ib, characterized by disturbed glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in a ubiquitously expressed glucose-6-phosphate transporter (G6PT). --- Explanation: Review confirms neutropenia as a defining feature of GSD Ib caused by G6PT deficiency.

[PMID:31705665] [SUPPORT] GSD-Ib is an autosomal recessive disorder characterized by hypoglycemia, excessive glycogen accumulation in the liver and kidney, neutropenia, neutrophil dysfunction, and inflammatory bowel disease. --- Explanation: Review confirms neutropenia as a characteristic feature of GSD Ib.


MONDO:0002413

[PMID:20301489] [SUPPORT] Individuals with untreated GSD Ib are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. --- Explanation: GeneReviews describes recurrent infections as a consequence of neutropenia in GSD Ib.


MONDO:0002413

[PMID:20301489] [SUPPORT] Individuals with untreated GSD Ib are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. --- Explanation: GeneReviews describes oral and genital ulcers in untreated GSD Ib.


MONDO:0002413

[PMID:12373568] [SUPPORT] Of 26 subjects, 13 (50%) had anemia. --- Explanation: Long-term outcome study found anemia in 50% of GSD Ia subjects.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease --- Explanation: GeneReviews lists osteoporosis as a long-term complication of untreated GSD I.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout --- Explanation: GeneReviews lists gout as a long-term complication of untreated GSD I.


MONDO:0002413

[PMID:12373568] [SUPPORT] Urinary albumin excretion was increased (>20 micro g/min) in 31% of subjects; two subjects had clinical albuminuria (>300 mg per 24 h), but none has progressed to chronic renal insufficiency. --- Explanation: Long-term outcome study documents microalbuminuria/proteinuria in 31% of GSD Ia subjects.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure) --- Explanation: GeneReviews lists renal disease including kidney failure as a long-term complication.


MONDO:0002413

[PMID:20301489] [SUPPORT] Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. --- Explanation: GeneReviews confirms fat accumulation in the liver as a core feature.


MONDO:0002413

[PMID:20301489] [SUPPORT] Xanthoma and diarrhea may be present. --- Explanation: GeneReviews notes diarrhea as a possible presentation.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout, systemic hypertension, pulmonary hypertension, hepatic adenomas with potential for malignancy, pancreatitis --- Explanation: GeneReviews lists pancreatitis as a long-term complication.


MONDO:0002413

[PMID:20301489] [SUPPORT] untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. --- Explanation: GeneReviews notes seizures as a presentation of severe hypoglycemia in untreated GSD I infants.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease --- Explanation: GeneReviews lists delayed puberty as a long-term complication of untreated GSD I.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout, systemic hypertension, pulmonary hypertension --- Explanation: GeneReviews lists systemic hypertension as a long-term complication.


MONDO:0002413

[PMID:20301489] [SUPPORT] Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout, systemic hypertension, pulmonary hypertension --- Explanation: GeneReviews lists pulmonary hypertension as a long-term complication.


MONDO:0002413

[PMID:20301489] [SUPPORT] Xanthoma and diarrhea may be present. --- Explanation: GeneReviews notes xanthoma as a possible clinical feature.


MONDO:0002413

[PMID:20301489] [SUPPORT] Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. --- Explanation: GeneReviews describes menorrhagia as a consequence of bleeding diathesis in GSD I females.


MONDO:0002413

[PMID:20301489] [INDIRECT EVIDENCE] [SUPPORT] Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. --- Explanation: GeneReviews entry describes the core metabolic pathophysiology of GSD I including glycogen and fat accumulation and fasting hypoglycemia.

[PMID:29663270] [INDIRECT EVIDENCE] [SUPPORT] In gluconeogenic organs, functional coupling of G6PT and G6Pase-α is required to maintain interprandial blood glucose homeostasis. --- Explanation: Review explains how G6PT/G6Pase-alpha coupling is required for glucose production between meals.


MONDO:0002413


MONDO:0002413

[PMID:26001652] [INDIRECT EVIDENCE] [SUPPORT] Evidence accumulates that poor metabolic control is a risk factor for the development of long-term complications, such as liver adenomas, low bone density/osteoporosis, and kidney disease in GSD I. --- Explanation: Review confirms that secondary metabolic derangements from poor metabolic control drive long-term complications.


MONDO:0002413

[PMID:19741523] [INDIRECT EVIDENCE] [SUPPORT] Loss of G6PT activity leads to enhanced endoplasmic reticulum stress, oxidative stress, and apoptosis that underlie neutropenia and neutrophil dysfunction in glycogen storage disease type Ib. --- Explanation: Review of GSD Ib neutropenia mechanisms demonstrates that G6PT deficiency causes ER stress and apoptosis in neutrophils.

[PMID:31705665] [INDIRECT EVIDENCE] [SUPPORT] GSD-Ib is an autosomal recessive disorder characterized by hypoglycemia, excessive glycogen accumulation in the liver and kidney, neutropenia, neutrophil dysfunction, and inflammatory bowel disease. GSD-Ib is caused by a deficiency of glucose-6-phosphate transporter (G6PT). --- Explanation: Review confirms that G6PT deficiency in GSD Ib causes both metabolic and immune manifestations including neutropenia and IBD.


MONDO:0002413

[PMID:12373570] [INDIRECT EVIDENCE] [SUPPORT] Hepatic adenomas occur in 22%-75% of affected adults, according to the population studied, and from those reported in the literature are thought to have an approximately 10% risk of undergoing malignant transformation. --- Explanation: Review of GSD I hepatic adenomas documents prevalence and malignant transformation risk.

[PMID:12373570] [INDIRECT EVIDENCE] [SUPPORT] the incidence of liver tumours in younger adults seems less than in older ones, suggesting that better dietary treatment, and thus improved metabolic control, may be protective. --- Explanation: Evidence that improved metabolic control reduces hepatic adenoma development.


MAXO:0000088

[PMID:12373568] [SUPPORT] The achievement of optimal biochemical control of glycogen storage disease type 1a continues to be a challenge, but is attainable by meticulous adherence to an individualized dietary regimen based on the results of periodic metabolic evaluation and home blood glucose monitoring. --- Explanation: Long-term study demonstrates that cornstarch-based dietary therapy can achieve metabolic control, though it remains challenging.


MAXO:0000058

[PMID:20301489] [SUPPORT] Human granulocyte colony-stimulating factor (G-CSF) for neutropenia, recurrent infections, enterocolitis and bowel ulcers. --- Explanation: GeneReviews recommends G-CSF for GSD Ib neutropenia and its complications.


MAXO:0000058

[PMID:38277989] [SUPPORT] Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). --- Explanation: International consensus confirms empagliflozin as a mechanism-based treatment for GSD Ib neutropenia.

[PMID:38277989] [SUPPORT] We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. --- Explanation: Consensus dosing recommendation for empagliflozin in GSD Ib.


MAXO:0000058

[PMID:20301489] [SUPPORT] allopurinol to prevent and/or treat gout --- Explanation: GeneReviews recommends allopurinol for hyperuricemia and gout management.


MAXO:0000058

[PMID:20301489] [SUPPORT] lipid-lowering medications for hyperlipidemia --- Explanation: GeneReviews recommends lipid-lowering medications for persistent hyperlipidemia.


MAXO:0000058

[PMID:20301489] [SUPPORT] angiotensin-converting enzyme inhibitors to treat microalbuminuria --- Explanation: GeneReviews recommends ACE inhibitors for renal protection.


MAXO:0001175

[PMID:12373570] [SUPPORT] Surgery (partial hepatectomy or orthotopic liver transplantation) is the definitive therapy for these tumours --- Explanation: Review confirms liver transplantation as definitive therapy for hepatic adenomas in GSD I.


MAXO:0000088

[PMID:20301489] [SUPPORT] citrate supplementation to prevent urinary calculi or ameliorate nephrocalcinosis --- Explanation: GeneReviews recommends citrate supplementation for renal complications.


MAXO:0010039

[PMID:20301489] [SUPPORT] kidney transplantation for end-stage kidney disease, and combined kidney and liver transplant when needed. --- Explanation: GeneReviews recommends kidney transplantation for end-stage kidney disease.


MAXO:0001001

[PMID:29663270] [SUPPORT] The results demonstrate that the liver-directed gene transfer and expression safely corrects metabolic abnormalities and prevents hepatocellular adenoma (HCA) development. --- Explanation: Preclinical study demonstrates efficacy of AAV gene therapy in murine GSD Ib.


MAXO:0000079

[PMID:20301489] [SUPPORT] Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both pathogenic variants have been identified in an affected family member. --- Explanation: GeneReviews describes genetic counseling and testing options.


HGNC.SYMBOL:G6PC1

[PMID:20301489] [SUPPORT] The diagnosis of GSD I is established in a proband by identification of biallelic pathogenic variants in either G6PC1 (GSD Ia) or SLC37A4 (GSD Ib). --- Explanation: GeneReviews confirms G6PC1 as the causative gene for GSD Ia.


HGNC.SYMBOL:SLC37A4

[PMID:20301489] [SUPPORT] The diagnosis of GSD I is established in a proband by identification of biallelic pathogenic variants in either G6PC1 (GSD Ia) or SLC37A4 (GSD Ib). --- Explanation: GeneReviews confirms SLC37A4 as the causative gene for GSD Ib.

[PMID:29663270] [SUPPORT] Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose-6-phosphate (G6P) transporter (G6PT or SLC37A4). --- Explanation: Review confirms SLC37A4 encodes G6PT and its deficiency causes GSD Ib.


MONDO:0002413

[PMID:20301489] [SUPPORT] GSD I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. --- Explanation: GeneReviews entry confirms autosomal recessive inheritance pattern for GSD I.


MONDO:0007187

[PMID:19032739] [SUPPORT] BCCs (varying clinically from flesh-colored papules to ulcerating plaques and in diameter from 1 to 10 mm) are most commonly located on the face, back and chest. The number of BBCs varies from a few to several thousand. --- Explanation: Documents variable presentation and multiplicity of BCCs in Gorlin syndrome.


MONDO:0007187

[PMID:19032739] [PARTIAL] Main clinical manifestations include multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles --- Explanation: Documents palmar manifestations as a main clinical feature of Gorlin syndrome.


MONDO:0007187


MONDO:0007187

[PMID:19032739] [SUPPORT] Recurrent jaw cysts occur in 90% of patients. --- Explanation: Documents high frequency of odontogenic keratocysts in Gorlin syndrome.


MONDO:0007187

[PMID:19032739] [SUPPORT] Main clinical manifestations include multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles, skeletal abnormalities, intracranial ectopic calcifications --- Explanation: Lists intracranial ectopic calcifications as a main clinical manifestation.


MONDO:0007187

[PMID:25403219] [SUPPORT] Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma. --- Explanation: Quantifies medulloblastoma risk by genotype, showing much higher risk in SUFU carriers.

[PMID:29186568] [SUPPORT] Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo). --- Explanation: Documents early onset of medulloblastoma in SUFU mutation carriers.

[PMID:32747535] [SUPPORT] We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. --- Explanation: iPSC model demonstrates that Gorlin patient-derived neural stem cells can form medulloblastoma-like tumors.


MONDO:0007187

[PMID:19032739] [INDIRECT EVIDENCE] [PARTIAL] NBCCS is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. --- Explanation: Establishes PTCH1 as the causative gene for NBCCS with autosomal dominant inheritance.

[PMID:28596197] [INDIRECT EVIDENCE] [PARTIAL] Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. --- Explanation: Confirms PTCH1 germline variants as the primary genetic cause of Gorlin syndrome.


MONDO:0007187

[PMID:25403219] [INDIRECT EVIDENCE] [SUPPORT] We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. --- Explanation: Demonstrates that SUFU mutations confer dramatically higher medulloblastoma risk than PTCH1 mutations.

[PMID:29186568] [INDIRECT EVIDENCE] [SUPPORT] Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma. --- Explanation: Confirms high medulloblastoma risk and poor prognosis in SUFU mutation carriers.


MAXO:0000004


MAXO:0000058

[PMID:22670904] [SUPPORT] Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. --- Explanation: Randomized controlled trial demonstrating efficacy of vismodegib in reducing BCC burden in Gorlin syndrome.

[PMID:22670904] [PARTIAL] The adverse events associated with treatment led to discontinuation in over half of treated patients. --- Explanation: Documents significant tolerability issues with vismodegib leading to high discontinuation rates.


CHEBI:66903

[PMID:22670904] [INDIRECT EVIDENCE] [SUPPORT] Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. --- Explanation: Randomized controlled trial demonstrating efficacy of vismodegib in reducing BCC burden in Gorlin syndrome.

[PMID:22670904] [INDIRECT EVIDENCE] [PARTIAL] The adverse events associated with treatment led to discontinuation in over half of treated patients. --- Explanation: Documents significant tolerability issues with vismodegib leading to high discontinuation rates.


MAXO:0000058


CHEBI:90863


MAXO:0000453


MAXO:0000055


MAXO:0000079


HGNC.SYMBOL:PTCH1

[PMID:28596197] [PARTIAL] A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. --- Explanation: Supports predominance of non-SUFU pathogenic variants in this cohort, but the snippet does not explicitly name PTCH1 in the quoted text.

[PMID:28596197] [SUPPORT] Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants. --- Explanation: Demonstrates genotype-phenotype correlation with milder disease in missense variant carriers.