MONDO:0012392

[PMID:12837870] [SUPPORT] One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy.
 --- Explanation: Two of the earliest described patients showed motor developmental delay or cerebral palsy.

[PMID:30730842] [SUPPORT] Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive.
 --- Explanation: Literature review confirms developmental delay as a recognized phenotype of symptomatic SBCADD.


MONDO:0012392

[PMID:30730842] [SUPPORT] Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive.
 --- Explanation: Seizures listed as a recognized presenting feature of symptomatic SBCADD.

[PMID:30730842] [SUPPORT] On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop.
 --- Explanation: Epilepsy can develop on longitudinal follow-up in symptomatic cases.


MONDO:0012392

[PMID:12837870] [SUPPORT] Except for 1 patient who developed mild muscle hypotonia, all patients remain asymptomatic at ages ranging from 3 to 14 months of age.
 --- Explanation: Reports mild muscle hypotonia in one of the newborn-screening- identified Hmong patients.

[PMID:30730842] [SUPPORT] Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive.
 --- Explanation: Hypotonia listed among presenting features in the literature review.


MONDO:0012392

[PMID:30730842] [SUPPORT] Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive.
 --- Explanation: Failure to thrive listed among presenting features in the literature review of 162 patients.


MONDO:0012392

[PMID:30730842] [SUPPORT] On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop.
 --- Explanation: Microcephaly listed as a feature that can develop on longitudinal follow-up.


MONDO:0012392

[PMID:30730842] [SUPPORT] On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop.
 --- Explanation: Autism listed among features that can develop on longitudinal follow-up in SBCADD.


MONDO:0012392

[PMID:12837870] [SUPPORT] One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy.
 --- Explanation: Directly reports athetoid cerebral palsy in one of the first described SBCADD patients.


MONDO:0012392

[PMID:12837870] [SUPPORT] One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy.
 --- Explanation: Directly reports muscle atrophy in an early SBCADD patient.


MONDO:0012392


MONDO:0012392

[PMID:30730842] [SUPPORT] Increased urinary excretion of 2-methylbutyrylglycine (2MBG) is the hallmark of SBCAD deficiency.
 --- Explanation: Directly identifies elevated urinary 2-MBG as the hallmark of SBCADD.

[PMID:31555323] [SUPPORT] All patients who underwent urinary organic acid analysis showed elevation of 2-methylburtyrylglycine in urine.
 --- Explanation: Confirms universal 2-MBG elevation in confirmed SBCADD patients.


MONDO:0012392

[PMID:12837870] [INDIRECT EVIDENCE] [SUPPORT] 2-methylbutyryl-CoA dehydrogenase deficiency, also known as short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency, is a recently described autosomal recessive disorder of L-isoleucine metabolism.
 --- Explanation: Directly supports primary SBCAD/ACADSB molecular dysfunction in this disorder.


MONDO:0012392

[PMID:15615815] [INDIRECT EVIDENCE] [SUPPORT] Isolated excretion of 2-methylbutyrylglycine (2-MBG) is the hallmark of short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), a recently identified defect in the proximal pathway of L-isoleucine oxidation.
 --- Explanation: Confirms that SBCADD is a defect in the proximal pathway of L-isoleucine oxidation with 2-MBG as hallmark metabolite.


MONDO:0012392

[PMID:15615815] [INDIRECT EVIDENCE] [SUPPORT] Increased flux through the R-pathway may act as a safety valve for overflow of accumulating S-pathway metabolites and thereby mitigate the severity of SBCADD.
 --- Explanation: Directly supports the hypothesis that R-pathway flux compensates for the S-pathway block and explains the mild phenotype.

[PMID:15615815] [INDIRECT EVIDENCE] [SUPPORT] Approximately 40-46% of total 2-methylbutyric acid conjugates were in the form of the R-isomer, indicating significant metabolism via the R-pathway.
 --- Explanation: Quantifies the significant contribution of R-pathway metabolism in SBCADD patients.


MONDO:0012392

[PMID:30730842] [INDIRECT EVIDENCE] [SUPPORT] Catabolic situations can precipitate acute metabolic decompensation.
 --- Explanation: Directly supports that catabolic stress triggers decompensation in SBCADD.


MONDO:0012392

[PMID:37309295] [INDIRECT EVIDENCE] [SUPPORT] Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences.
 --- Explanation: Expert consensus statement from 2023 JIMD paper characterizing SBCAD deficiency as largely a biochemical abnormality.


MAXO:0000058

[PMID:30730842] [SUPPORT] Carnitine supplementation and valproate avoidance appear to be indicated.
 --- Explanation: Directly recommends carnitine supplementation as an indicated treatment for SBCADD.

[PMID:30730842] [SUPPORT] Longitudinal biochemical monitoring of the two patients while on treatment with carnitine (100 mg/kg/day) was provided.
 --- Explanation: Reports specific carnitine dosing of 100 mg/kg/day with biochemical monitoring.


MAXO:0000950

[PMID:30730842] [SUPPORT] Providing an emergency protocol for the management of acute catabolic episodes seems reasonable in asymptomatic patients with SBCAD deficiency.
 --- Explanation: Directly supports emergency protocol provision for catabolic stress management.

[PMID:30730842] [SUPPORT] Catabolic situations can precipitate acute metabolic decompensation.
 --- Explanation: Supports the rationale for catabolic stress avoidance.


MAXO:0000088

[PMID:12837870] [SUPPORT] Dietary treatment was initiated in the neonatal period. Except for 1 patient who developed mild muscle hypotonia, all patients remain asymptomatic at ages ranging from 3 to 14 months of age.
 --- Explanation: Reports early dietary treatment in newborn-screening-identified Hmong patients with good short-term outcomes.

[PMID:12837870] [PARTIAL] The continued efficacy of long-term dietary therapy instituted presymptomatically remains to be established.
 --- Explanation: Notes that long-term efficacy of presymptomatic dietary treatment is unproven.


MAXO:0000058

[PMID:30730842] [SUPPORT] Carnitine supplementation and valproate avoidance appear to be indicated.
 --- Explanation: Directly recommends valproate avoidance as an indicated measure in SBCADD management.


MAXO:0000124

[PMID:12837870] [SUPPORT] These cases suggest that SBCAD deficiency is another inborn error of metabolism detectable by newborn screening using tandem mass spectrometry.
 --- Explanation: Establishes that SBCADD is detectable by tandem MS newborn screening.


MAXO:0000079

[PMID:12837870] [SUPPORT] A sibling of the first patient is asymptomatic after prenatal diagnosis and early treatment.
 --- Explanation: Demonstrates prenatal diagnosis has been applied in SBCADD families, supporting the role of genetic counseling.


MAXO:0000950

[PMID:30730842] [SUPPORT] Longitudinal follow-up is recommended.
 --- Explanation: Directly recommends longitudinal follow-up in SBCADD.


HGNC.SYMBOL:ACADSB pathogenic variants

[PMID:20547083] [SUPPORT] Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, also known as 2-methylbutyryl-CoA dehydrogenase deficiency, is a recently described autosomal recessive disorder of isoleucine metabolism. Most patients reported thus far have originated from a founder mutation in the Hmong Chinese population.
 --- Explanation: Confirms the genetic basis and founder mutation background of SBCADD.

[PMID:16950638] [SUPPORT] Confirmation of diagnosis is therefore advisable by specific enzyme assay and/or mutation analysis of the ACAT1 (beta-KT), ACADSB (SBCAD) or HADH2 (MHBD) genes.
 --- Explanation: Confirms ACADSB as the gene for molecular diagnosis of SBCADD.


MONDO:0018923

[PMID:20301696] [SUPPORT] congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus) --- Explanation: GeneReviews documents the spectrum of conotruncal defects.


MONDO:0018923

[PMID:20301696] [PARTIAL] serum ionized calcium every three to six months in infancy, every five years through childhood, every one to two years thereafter, preoperatively and postoperatively, and regularly during pregnancy --- Explanation: Frequent calcium monitoring is recommended across the lifespan, reflecting the persistent risk of hypocalcemia from parathyroid hypoplasia.


MONDO:0018923


MONDO:0018923

[PMID:20301696] [SUPPORT] palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate) --- Explanation: Palatal abnormalities are a major manifestation.


MONDO:0018923

[PMID:11242110] [PARTIAL] cleft palate --- Explanation: Cleft palate is observed in Tbx1 knockout mice.


MONDO:0018923

[PMID:20301696] [PARTIAL] learning difficulties --- Explanation: Learning difficulties are documented as a major manifestation.


MONDO:0018923

[PMID:20301696] [PARTIAL] Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS --- Explanation: Psychiatric illness including schizophrenia is elevated.


MONDO:0018923

[PMID:11242110] [INDIRECT EVIDENCE] [PARTIAL] mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome --- Explanation: Tbx1 heterozygous mice recapitulate the cardiac phenotype of human 22q11.2DS.

[PMID:11242110] [INDIRECT EVIDENCE] [SUPPORT] Tbx1-/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of the thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae and cleft palate --- Explanation: Homozygous Tbx1 knockout recapitulates the full DiGeorge phenotype.


MONDO:0018923

[PMID:20301696] [INDIRECT EVIDENCE] [PARTIAL] congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus) --- Explanation: GeneReviews documents the characteristic cardiac malformations.


MONDO:0018923

[PMID:20301696] [INDIRECT EVIDENCE] [PARTIAL] The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. --- Explanation: Immune deficiency is listed as one of the major clinical manifestations of 22q11.2DS.


MAXO:0000004

[PMID:20301696] [PARTIAL] Cardiac anomalies are treated as recommended by cardiologist --- Explanation: Cardiac management is part of standard care.


MAXO:0000088

[PMID:20301696] [SUPPORT] calcium supplementation and referral to an endocrinologist --- Explanation: Calcium supplementation is recommended for hypocalcemia.


MAXO:0010039

[PMID:20301696] [SUPPORT] rarely, prophylactic antibiotics, IVIG therapy, or thymus tissue implantation are required --- Explanation: Thymus transplantation is indicated for complete DiGeorge.


MAXO:0000930

[PMID:20301696] [SUPPORT] speech therapy --- Explanation: Speech therapy is part of the recommended management.


HGNC.SYMBOL:22q11.2 microdeletion

[PMID:20301696] [SUPPORT] the deletion is de novo in more than 90% of individuals and inherited from a heterozygous parent in about 10% of individuals --- Explanation: GeneReviews documents the de novo vs inherited proportion.


HGNC.SYMBOL:TBX1 haploinsufficiency

[PMID:11242110] [PARTIAL] we propose that TBX1 in humans is a key gene in the etiology of DGS/VCFS --- Explanation: Mouse knockout studies established TBX1 as the critical gene.


MONDO:0009520

[PMID:35646072] [SUPPORT] 49 patients (79.03%) developed metabolic acidosis. --- Explanation: Quantifies metabolic acidosis frequency at 79% in a large molecularly confirmed cohort.

[PMID:32059735] [SUPPORT] More than 95% of patients presented with acute metabolic decompensation. --- Explanation: Systematic review confirms near-universal metabolic decompensation with acidosis.


MONDO:0009520

[PMID:35646072] [SUPPORT] 38 patients (61.29%) presented with hypoglycemia --- Explanation: Quantifies hypoglycemia at diagnosis in 61% of a 62-patient cohort.

[PMID:3099065] [SUPPORT] In the first year of life infants with HMG-CoA-LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. --- Explanation: Foundational review emphasizing life-threatening hypoglycemia in infancy.


MONDO:0009520

[PMID:23861731] [SUPPORT] Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. --- Explanation: Hyperammonemia demonstrated mechanistically in the liver-specific HMGCL KO mouse model.


MONDO:0009520

[PMID:35646072] [SUPPORT] Common neurological findings include seizures 17/62 (27.41%) --- Explanation: Quantifies seizure frequency at 27.4% in a 62-patient cohort.


MONDO:0009520


MONDO:0009520

[PMID:32059735] [SUPPORT] The neurologic long-term outcome was favorable with 62.6% of patients showing normal development. --- Explanation: Most patients develop normally, but a significant minority has long-term neurologic sequelae.


MONDO:0009520

[PMID:35646072] [SUPPORT] An MRI of the brain exhibited nonspecific periventricular and deep white matter hyperintense signal changes in 16 patients (25.80%) --- Explanation: Quantifies white matter abnormality frequency at 25.8% in the cohort.


MONDO:0009520

[PMID:35646072] [SUPPORT] hypotonic 3/62 (4.83%) --- Explanation: Quantifies hypotonia in the 62-patient cohort.


MONDO:0009520

[PMID:35646072] [SUPPORT] speech delay 7/62 (11.29%) --- Explanation: Quantifies speech delay frequency in a molecularly confirmed cohort.


MONDO:0009520

[PMID:35646072] [SUPPORT] cerebral atrophy was found in one (1/62; 1.612%) patient. --- Explanation: Quantifies cerebral atrophy as a rare but documented finding.


MONDO:0009520

[PMID:36771238] [SUPPORT] there were two patients that presented atypically-one with fulminant liver failure and the other with isolated developmental delay. --- Explanation: Documents fulminant liver failure as an atypical presentation of HMGCLD.


MONDO:0009520

[PMID:32059735] [INDIRECT EVIDENCE] [SUPPORT] 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in HMGCL. --- Explanation: Supports HMGCL molecular deficiency as the initiating genetic and enzymatic defect.


MONDO:0009520

[PMID:32059735] [INDIRECT EVIDENCE] [SUPPORT] More than 95% of patients presented with acute metabolic decompensation. Most patients manifested within the first year of life, 42.4% already neonatally. --- Explanation: Systematic review of 211 patients demonstrates near-universal acute metabolic crises from ketogenesis failure.


MONDO:0009520

[PMID:36771238] [INDIRECT EVIDENCE] [SUPPORT] 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. --- Explanation: Confirms the clinical presentation from toxic metabolite accumulation.


MONDO:0009520

[PMID:23861731] [INDIRECT EVIDENCE] [SUPPORT] Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. --- Explanation: Demonstrates acyl-CoA disruption as a core pathological mechanism in liver-specific HMGCL KO mice.

[PMID:23861731] [INDIRECT EVIDENCE] [SUPPORT] KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function --- Explanation: Confirms acetyl-CoA-linked mechanism for secondary hyperammonemia and carglumate responsiveness.


MONDO:0009520

[PMID:39062136] [INDIRECT EVIDENCE] [SUPPORT] HMG decreased the activities of succinate dehydrogenase and respiratory chain complexes II-III and IV in the cortex. HMG also decreased the activities of citrate synthase and succinate dehydrogenase, as well as complex IV in the striatum. --- Explanation: Quantitative evidence of HMG-mediated bioenergetic disruption in brain regions.

[PMID:39062136] [INDIRECT EVIDENCE] [SUPPORT] HMG further increased DRP1 levels in the cortex, indicating mitochondrial fission. --- Explanation: Demonstrates HMG drives mitochondrial network fragmentation in brain tissue.

[PMID:39062136] [INDIRECT EVIDENCE] [SUPPORT] HMG-injected animals showed impaired performance in all sensorimotor tests examined. --- Explanation: Links HMG exposure directly to neurodevelopmental impairment in an animal model.


MAXO:0000088

[PMID:36771238] [SUPPORT] All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. --- Explanation: Confirms universal use of protein restriction in contemporary management.

[PMID:35646072] [SUPPORT] Our findings suggest that diagnosis at an early stage with careful dietary management may avoid metabolic crises. --- Explanation: Large cohort supporting dietary management for crisis prevention.


MAXO:0000088

[PMID:3099065] [SUPPORT] The metabolic crisis develops when the infant is first introduced to dietary protein soon after birth, or later, when a reduced intake of glucose, often during a viral infection, results in a drain on the infant's circulating glucose levels. --- Explanation: Identifies fasting and reduced glucose intake as key crisis triggers.


MAXO:0000058

[PMID:36771238] [SUPPORT] Most patients take L-carnitine. --- Explanation: Confirms widespread use of carnitine supplementation in HMGCLD management.


MAXO:0000058

[PMID:36771238] [SUPPORT] five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids --- Explanation: Documents high-dose exogenous ketone use in acute management.


MAXO:0000950

[PMID:3099065] [SUPPORT] In the first year of life infants with HMG-CoA-LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. --- Explanation: Foundational evidence for the critical importance of prompt acute intervention.

[PMID:36771238] [SUPPORT] Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder. --- Explanation: Contemporary confirmation that rapid supportive care is essential for survival.


MAXO:0000124

[PMID:35646072] [SUPPORT] Our findings suggest that diagnosis at an early stage with careful dietary management may avoid metabolic crises. --- Explanation: Supports early detection and treatment to prevent metabolic crises.


MAXO:0000079

[PMID:32059735] [SUPPORT] 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in HMGCL. --- Explanation: Autosomal recessive etiology supports genetic counseling for affected families.


MAXO:0000058

[PMID:23861731] [SUPPORT] KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function --- Explanation: Demonstrates carglumate efficacy for hyperammonemia in the HMGCL KO mouse model.


HGNC.SYMBOL:HMGCL pathogenic variants

[PMID:32059735] [SUPPORT] This comprehensive data analysis provides a systematic overview on all published cases with HMGCLD including a list of all known HMGCL mutations. --- Explanation: Provides the most comprehensive catalog of HMGCL mutations and associated phenotypes.

[PMID:35646072] [SUPPORT] This is the largest cohort of HMGCLD patients reported from Saudi Arabia, signifying this disorder as a likely life-threatening disease, with a high prevalence in the region. --- Explanation: Largest regional cohort demonstrating population-specific variant enrichment.


MONDO:0014706

[PMID:26320891] [SUPPORT] recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features --- Explanation: All eight patients in the original cohort displayed cutis laxa with progeroid features.


MONDO:0014706

[PMID:25077174] [SUPPORT] bilateral cataracts have been seen in 6/10 cases and so appear more frequent than in patients with PYCR1 mutations --- Explanation: Cataracts are a frequent ophthalmological feature of ALDH18A1-related disorders, reported in the majority of cases.


MONDO:0014706


MONDO:0014706

[PMID:26320891] [INDIRECT EVIDENCE] [SUPPORT] we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation --- Explanation: Fibroblast studies demonstrate that Arg138 mutations reduce P5CS activity and proline production through a dominant-negative mechanism.

[PMID:26320891] [INDIRECT EVIDENCE] [SUPPORT] the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution --- Explanation: Biochemical evidence supports dominant-negative mechanism rather than simple haploinsufficiency.


MAXO:0000079


MAXO:0000950


hgnc:9722

[PMID:26320891] [SUPPORT] We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. --- Explanation: Identifies the recurrent Arg138 mutations as the molecular basis of ADCL3.

[PMID:28228640] [SUPPORT] This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. --- Explanation: Expands the mutational spectrum of ADCL3 beyond the Arg138 hotspot.


MONDO:0014706

[PMID:26320891] [SUPPORT] A de novo origin was confirmed in all six probands for whom parental DNA was available. --- Explanation: The landmark paper establishing ADCL3 confirms de novo origin of all characterized mutations.

[PMID:28228640] [SUPPORT] We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 --- Explanation: Additional case report confirms de novo dominant inheritance at a residue other than Arg138.


MONDO:0100126

[PMID:26026163] [SUPPORT] we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia --- Explanation: Spastic paraplegia is the defining feature of SPG9A, ranging from pure to complex forms.


MONDO:0100126

[PMID:26026163] [SUPPORT] we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality --- Explanation: SPG9B is characterized by complex HSP with prominent cognitive impairment.


MONDO:0100126

[PMID:31402623] [SUPPORT] SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits --- Explanation: Cognitive impairment is a defining feature distinguishing SPG9B severity from SPG9A.


MONDO:0100126

[PMID:36067040] [SUPPORT] These four patients exhibit variable developmental delay, neurological deficits and loose skin. --- Explanation: Developmental delay is a consistent feature of biallelic ALDH18A1 disease.


MONDO:0100126

[PMID:24767728] [SUPPORT] Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. --- Explanation: Cutis laxa is a recognized feature of ARCL3A with variable distribution.


MONDO:0100126

[PMID:25077174] [SUPPORT] bilateral cataracts have been seen in 6/10 cases and so appear more frequent than in patients with PYCR1 mutations --- Explanation: Cataracts are a common feature of ALDH18A1-related disorders, more frequent than in the related PYCR1-related cutis laxa.


MONDO:0100126

[PMID:24767728] [SUPPORT] Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. --- Explanation: Short stature and failure to thrive are consistent features of ARCL3A.


MONDO:0100126

[PMID:25077174] [SUPPORT] Microcephaly has been reported in 7/10 cases, a similar proportion to that seen in patients with PYCR1 mutations. --- Explanation: Microcephaly is a frequent neurological feature of ARCL3A.


MONDO:0100126

[PMID:26026163] [INDIRECT EVIDENCE] [SUPPORT] Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. --- Explanation: Metabolic profiling demonstrates reduced amino acid levels downstream of P5CS.

[PMID:36067040] [INDIRECT EVIDENCE] [SUPPORT] we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione --- Explanation: Metabolomics in patient fibroblasts confirms broad impairment of glutamate-derived amino acid and antioxidant pathways.


MONDO:0100126


MONDO:0100126

[PMID:36067040] [INDIRECT EVIDENCE] [SUPPORT] Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. --- Explanation: Decreased putrescine biosynthesis demonstrates P5CS deficiency impacts antioxidant pathways beyond proline synthesis.


MAXO:0000079

[PMID:26026163] [SUPPORT] we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes --- Explanation: Authors recommend metabolic screening as part of the diagnostic approach for HSP.


hgnc:9722

[PMID:29754261] [SUPPORT] Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa. --- Explanation: Establishes that ALDH18A1 mutations cause both dominant and recessive forms of spastic paraplegia and cutis laxa.

[PMID:26026163] [SUPPORT] ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. --- Explanation: Defines the enzymatic function of the ALDH18A1 gene product.


MONDO:0100126

[PMID:26026163] [SUPPORT] we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia --- Explanation: Identifies monoallelic ALDH18A1 mutations in autosomal dominant pedigrees.


MONDO:0100126

[PMID:26026163] [SUPPORT] we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality --- Explanation: Identifies biallelic ALDH18A1 mutations in autosomal recessive spastic paraplegia families.

[PMID:24767728] [SUPPORT] Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. --- Explanation: Confirms autosomal recessive inheritance for ALDH18A1-related cutis laxa.


MONDO:0005061


MONDO:0005061

[PMID:27637426] [INDIRECT EVIDENCE] [SUPPORT] An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. --- Explanation: This abstract states that ALK rearrangements drive a subset of NSCLC, supporting the ALK gene rearrangement mechanism.


MAXO:0000058


CHEBI:90936


CHEBI:143117


CHEBI:232810


CHEBI:64310


MAXO:0000647


HGNC.SYMBOL:ALK


HGNC.SYMBOL:EML4


MONDO:0005061

[PMID:32657049] [SUPPORT] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0010958

[PMID:15178757] [SUPPORT] Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death --- Explanation: Bradycardia is listed among the cardiac manifestations of ankyrin-B syndrome.


MONDO:0010958

[PMID:15178757] [SUPPORT] Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death --- Explanation: Idiopathic ventricular fibrillation is a recognized cardiac manifestation.


MONDO:0010958

[PMID:15178757] [SUPPORT] Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death --- Explanation: CPVT is part of the arrhythmia spectrum in ankyrin-B syndrome.


MONDO:0010958

[PMID:15178757] [PARTIAL] a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes --- Explanation: QT prolongation occurs in some but not all carriers, hence the reclassification from LQT4 to ankyrin-B syndrome.


MONDO:0010958

[PMID:35990955] [SUPPORT] Certain loss-of-function ANK2 variants are associated with a primarily cardiac-presenting autosomal-dominant condition with incomplete penetrance and variable expressivity characterized by a predisposition to supraventricular and ventricular arrhythmias, arrhythmogenic cardiomyopathy, congenital and adult-onset structural heart disease, and sudden death --- Explanation: Comprehensive review establishing the broad arrhythmia susceptibility in ankyrin-B syndrome.


MONDO:0010958

[PMID:17242276] [PARTIAL] the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death --- Explanation: Snippet describes the clinical severity spectrum but does not explicitly mention syncope; syncope is inferred as an intermediate presentation between asymptomatic carriers and sudden death.


MONDO:0010958

[PMID:15178757] [SUPPORT] Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death --- Explanation: Sudden death is a recognized risk of ankyrin-B syndrome.


MONDO:0010958

[PMID:37195288] [SUPPORT] We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy --- Explanation: Clinical cohort of 12 patients with ANK2 LOF variants shows early-onset epilepsy as a core feature.


MONDO:0010958

[PMID:37195288] [SUPPORT] We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy --- Explanation: Intellectual disability is a core feature of the ANK2-associated neurodevelopmental syndrome.


MONDO:0010958

[PMID:39631164] [SUPPORT] Evidence from exome sequencing studies have repeatedly implicated rare variants in ANK2 in autism spectrum disorder --- Explanation: ANK2 is established as a high-confidence ASD risk gene.

[PMID:31285321] [SUPPORT] Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function --- Explanation: Mouse model recapitulates social and communicative behavioral deficits relevant to ASD.


MONDO:0010958

[PMID:12571597] [INDIRECT EVIDENCE] [SUPPORT] Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level --- Explanation: Demonstrates that ankyrin-B mutation disrupts the localization of multiple ion channels and transporters at T-tubule/SR sites in cardiomyocytes.

[PMID:12571597] [INDIRECT EVIDENCE] [SUPPORT] Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia --- Explanation: Links ankyrin-B mutation to altered calcium signaling and extrasystoles as the mechanism underlying arrhythmia.


MONDO:0010958


MONDO:0010958

[PMID:31285321] [INDIRECT EVIDENCE] [SUPPORT] We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. --- Explanation: Directly demonstrates that giant ankyrin-B mutation promotes increased axon branching and ectopic connectivity in the mouse model.


MONDO:0010958

[PMID:37195288] [INDIRECT EVIDENCE] [SUPPORT] hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network --- Explanation: Demonstrates that ANK2 haploinsufficiency in human neurons leads to hyperactive network activity.


MAXO:0000058


MAXO:0000079

[PMID:17242276] [SUPPORT] the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes --- Explanation: The extreme clinical variability necessitates careful genetic counseling for variant carriers and their families.


hgnc:493

[PMID:17242276] [SUPPORT] Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death --- Explanation: Comprehensive characterization of ANK2 variants establishes the spectrum of cardiac phenotypes and cellular loss-of-function activity.

[PMID:15178757] [SUPPORT] All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes --- Explanation: Establishes the molecular mechanism: all cardiac-associated mutations impair ankyrin-B scaffolding function for ion channels and transporters.


hgnc:493

[PMID:37195288] [SUPPORT] Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy --- Explanation: Defines the neurodevelopmental phenotype of de novo ANK2 loss-of-function variants in a cohort of 12 patients.

[PMID:39631164] [SUPPORT] The ANK2 gene, encoding ankyrin-B, is a high-confidence risk factor for neurodevelopmental disorders (NDDs) --- Explanation: Review establishing ANK2 as a high-confidence NDD risk gene based on cumulative genetic evidence.


MONDO:0010958

[PMID:15178757] [SUPPORT] A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome --- Explanation: Establishes dominant inheritance of ANK2-related cardiac arrhythmia.


MONDO:0012883


MONDO:0012883

[PMID:41580016] [INDIRECT EVIDENCE] [SUPPORT] Dysfunction of the retinoic acid (RA) signaling pathway, which is mediated by the formation of the PML-RARA fusion gene, plays a central role in the pathogenesis of acute promyelocytic leukemia (APL). --- Explanation: This abstract directly links PML-RARA fusion to APL pathogenesis, supporting the fusion oncogene mechanism.


CHEBI:15367


CHEBI:30621


MAXO:0000647


MAXO:0000950


HGNC.SYMBOL:PML-RARA Fusion


HGNC.SYMBOL:FLT3-ITD


MONDO:0012883

[PMID:397771] [SUPPORT] Acute promyelocytic leukemia (APL) is characterized by proliferation of --- Explanation: Abstract notes APL is characterized by proliferation of promyelocytes.


MONDO:0007100

[PMID:23239211] [SUPPORT] Peripheral neuropathy is a common complication of many of the systemic amyloidoses. --- Explanation: The literature indicates that peripheral neuropathy is a common complication of amyloidoses, which includes ATTR amyloidosis.

[PMID:35830843] [SUPPORT] The clinical manifestations of this mutation involve mainly limb sensory or motor disorders or gastrointestinal symptoms or both, and the electrophysiological examination shows neurogenic damage. --- Explanation: This study indicates that peripheral neuropathy, including sensory and motor disorders, is a frequent manifestation in patients with the TTR Val30Leu mutation, a form of familial amyloid polyneuropathy.

[PMID:31445300] [SUPPORT] Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a rare, life-threatening disease, caused by point mutations in the transthyretin gene. It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. --- Explanation: The literature confirms that hATTR amyloidosis frequently involves polyneuropathy, including sensory loss, numbness, tingling, and autonomic dysfunction.

[PMID:36504143] [NO_EVIDENCE] Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). --- Explanation: This study suggests that autonomic dysfunction is a common complication in small-fiber neuropathy, which can be seen in conditions like amyloidosis.


MONDO:0007100

[PMID:34694575] [NO_EVIDENCE] The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans. --- Explanation: The reference discusses the increased recognition and diagnosis of ATTR cardiac amyloidosis, supporting the statement that it is frequently diagnosed as a cardiovascular condition.

[PMID:35235819] [SUPPORT] Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction. --- Explanation: This reference supports the statement by listing heart failure, arrhythmias, and autonomic dysfunction (which includes orthostatic hypotension) as common sequelae of cardiac amyloidosis.

[PMID:38044190] [SUPPORT] Patients with TTRA had higher levels of ultrasensitive troponin I (TnI-US) and N-terminal brain natriuretic propeptide (NT-ProBNP); in electrocardiography (ECG) they presented a pseudo-infarction pattern more frequently as well as conduction disturbances. --- Explanation: The reference supports the frequent occurrence of cardiovascular manifestations in ATTR amyloidosis, including cardiomyopathy and arrhythmias.

[PMID:29770800] [SUPPORT] Cardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. --- Explanation: This reference supports the statement by describing the involvement of the myocardium (cardiomyopathy) and the frequent occurrence of cardiovascular symptoms in cardiac amyloidosis.

[PMID:38844297] [SUPPORT] Cardiac amyloidosis (CA), usually caused by deposition of misfolded transthyretin or immunoglobulin light chains, is an increasingly recognized cause of heart failure burdened by a poor prognosis. --- Explanation: This reference supports the statement by describing heart failure as a frequent sequela of ATTR amyloidosis.


MONDO:0007100

[PMID:28085522] [SUPPORT] We report on two elderly patients (an 80-year-old woman and an 83-year-old man) with progressive vitreous opacities (VOs) as the initial manifestation of hereditary transthyretin (ATTR Val30Met) carries, who had no evidence of systemic involvement or family history of amyloidosis and lived in non-endemic areas. --- Explanation: The reference provides evidence that vitreous opacities can be an initial manifestation in patients with hereditary transthyretin amyloidosis (ATTR Val30Met), supporting the statement that vitreous opacities occur occasionally in ATTR amyloidosis.

[PMID:36129270] [SUPPORT] However, 3 patients (43%) had worsening vitreous opacities in both eyes, and 4 patients (57%) developed secondary open-angle glaucoma. --- Explanation: The reference indicates that vitreous opacities were observed and worsened in some patients with ATTR amyloidosis, supporting the statement that vitreous opacities can occur occasionally in ATTR amyloidosis and lead to visual impairment.


MONDO:0007100

[PMID:22537653] [SUPPORT] Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. --- Explanation: The reference confirms that renal dysfunction, including proteinuria, is a clinical feature of transthyretin amyloidosis (ATTR).

[PMID:37997196] [SUPPORT] Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy that commonly presents with concomitant chronic kidney disease. --- Explanation: The reference supports the statement by indicating that chronic kidney disease, which encompasses renal dysfunction, is commonly associated with transthyretin cardiac amyloidosis (ATTR-CA).


MONDO:0007100

[PMID:35144512] [PARTIAL] Patients often reported problems with mobility, usual activities, pain/discomfort and anxiety/depression, but not with self-care. --- Explanation: The literature indicates that systemic amyloidosis, including ATTR, frequently impacts daily life and mobility, which can be associated with fatigue.

[PMID:31445300] [NO_EVIDENCE] It is a heterogeneous, multisystem disease with rapidly progressing polyneuropathy (including sensory, motor, and autonomic impairments) and cardiac dysfunction. --- Explanation: The literature describes ATTR amyloidosis as a multisystem disease, which can imply the presence of fatigue due to its systemic impact.

[PMID:33609196] [NO_EVIDENCE] Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function. --- Explanation: The progressive loss of function in various organs and tissues can lead to severe fatigue, limiting activities of daily living.

[PMID:35128833] [NO_EVIDENCE] Amyloidosis is a severe and fatal systemic disease, characterized by an accumulation of amyloid fibrils in various tissues/organs, including nerves, kidneys, gastrointestinal tract, and heart. --- Explanation: The systemic nature of ATTR amyloidosis affecting multiple organs can contribute to fatigue.


MONDO:0007100


MONDO:0007100

[PMID:34884963] [INDIRECT EVIDENCE] [SUPPORT] Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. --- Explanation: The abstract mentions that TTR amyloidogenesis involves the formation and aggregation of amyloid fibrils, which supports the statement that mutations in the TTR gene result in the production of unstable transthyretin proteins that misfold and aggregate into amyloid fibrils.

[PMID:35830843] [INDIRECT EVIDENCE] [PARTIAL] Familial amyloid polyneuropathy is currently prevalent worldwide as the transthyretin (TTR) Val30Met mutation, and there are other types of mutations. --- Explanation: This reference supports the statement by mentioning that familial amyloid polyneuropathy is caused by mutations in the TTR gene, which is consistent with the production of unstable transthyretin proteins that misfold and aggregate.

[PMID:38844302] [INDIRECT EVIDENCE] [PARTIAL] Hereditary transthyretin-related amyloidosis (hATTR) is the most common form of familial amyloidosis. It is an autosomal dominant disease caused by a pathogenic variant in the TTR gene. --- Explanation: This reference supports the statement by explaining that hereditary transthyretin-related amyloidosis is caused by pathogenic variants in the TTR gene.

[PMID:22471982] [INDIRECT EVIDENCE] [PARTIAL] hereditary transthyretin (TTR) amyloidosis which is a genetically transmitted disease that results from a mutation in the gene encoding the plasma TTR protein. --- Explanation: The abstract confirms that hereditary transthyretin amyloidosis results from mutations in the TTR gene, which aligns with the statement.

[PMID:29962408] [INDIRECT EVIDENCE] [SUPPORT] Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. --- Explanation: This reference explicitly states that hereditary transthyretin-related amyloidosis is caused by mutations in the TTR gene that destabilize the protein, supporting the statement.


MONDO:0007100

[PMID:31452023] [INDIRECT EVIDENCE] [PARTIAL] fibrillar deposits in a several organs including the heart, kidney, liver, and peripheral nerves cause organ dysfunction and associated morbidity and mortality. --- Explanation: The reference supports that amyloid fibrils deposit in the heart, kidney, and peripheral nerves, but does not mention the gastrointestinal tract.

[PMID:15126690] [INDIRECT EVIDENCE] [PARTIAL] It is possible that a common factor in the amyloidogenesis process exists among the different forms; this common factor can involve changes produced by mutations in the three-dimensional structure of TTR, rendering it prone to deposition as amyloid. --- Explanation: The reference supports that misfolded transthyretin proteins form amyloid fibrils but does not specify all the tissues mentioned in the statement.

[PMID:34018852] [INDIRECT EVIDENCE] [PARTIAL] Age-related wild-type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart, this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. --- Explanation: The reference supports that amyloid fibrils deposit in the heart and connective tissue, but does not mention the nerves, kidneys, or gastrointestinal tract.

[PMID:34361762] [INDIRECT EVIDENCE] [PARTIAL] Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. --- Explanation: The reference supports that amyloid fibrils deposit in the nerves and heart but does not mention the kidneys or gastrointestinal tract.


MAXO:0000058

[PMID:25872787] [SUPPORT] Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. --- Explanation: The study shows that tafamidis effectively stabilizes TTR, supporting the statement that it helps stabilize transthyretin.

[PMID:31098895] [SUPPORT] Tafamidis slowed deterioration of neurological function and maintained health-related quality of life in patients with early-stage ATTR-PN... TTR tetramers were stabilized in nearly all patients. --- Explanation: The evidence indicates that tafamidis stabilizes TTR tetramers, supporting the statement.

[PMID:26800456] [SUPPORT] Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. --- Explanation: The study supports that tafamidis is effective in stabilizing TTR and preventing amyloid fibril formation.

[PMID:29962408] [SUPPORT] The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. --- Explanation: The review supports that stabilizing TTR is crucial, and tafamidis is one of the compounds that achieve this.

[PMID:34609369] [SUPPORT] Several TTR molecule stabilizers were developed successfully... Silencing the TTR gene using different strategies is flourishing. --- Explanation: The article states that TTR stabilizers, including tafamidis, have been successfully developed, supporting the statement.


CHEBI:78538

[PMID:25872787] [INDIRECT EVIDENCE] [SUPPORT] Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. --- Explanation: The study shows that tafamidis effectively stabilizes TTR, supporting the statement that it helps stabilize transthyretin.

[PMID:31098895] [INDIRECT EVIDENCE] [SUPPORT] Tafamidis slowed deterioration of neurological function and maintained health-related quality of life in patients with early-stage ATTR-PN... TTR tetramers were stabilized in nearly all patients. --- Explanation: The evidence indicates that tafamidis stabilizes TTR tetramers, supporting the statement.

[PMID:26800456] [INDIRECT EVIDENCE] [SUPPORT] Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. --- Explanation: The study supports that tafamidis is effective in stabilizing TTR and preventing amyloid fibril formation.

[PMID:29962408] [INDIRECT EVIDENCE] [SUPPORT] The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. --- Explanation: The review supports that stabilizing TTR is crucial, and tafamidis is one of the compounds that achieve this.

[PMID:34609369] [INDIRECT EVIDENCE] [SUPPORT] Several TTR molecule stabilizers were developed successfully... Silencing the TTR gene using different strategies is flourishing. --- Explanation: The article states that TTR stabilizers, including tafamidis, have been successfully developed, supporting the statement.


MAXO:0000058

[PMID:30480471] [SUPPORT] Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. --- Explanation: The abstract clearly states that patisiran reduces the production of transthyretin protein, which aligns with the statement.

[PMID:37599395] [SUPPORT] Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). --- Explanation: The abstract mentions that patisiran, as an RNAi therapeutic, benefits patients with hereditary transthyretin amyloidosis, indicating its role in reducing transthyretin protein production.

[PMID:31131842] [SUPPORT] Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both mutant and wild-type amyloid transthyretin (ATTR) protein production becomes suppressed. --- Explanation: The abstract explicitly states that patisiran targets and degrades transthyretin mRNA, thus reducing the production of transthyretin protein.


NCIT:C116792

[PMID:30480471] [INDIRECT EVIDENCE] [SUPPORT] Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. --- Explanation: The abstract clearly states that patisiran reduces the production of transthyretin protein, which aligns with the statement.

[PMID:37599395] [INDIRECT EVIDENCE] [SUPPORT] Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). --- Explanation: The abstract mentions that patisiran, as an RNAi therapeutic, benefits patients with hereditary transthyretin amyloidosis, indicating its role in reducing transthyretin protein production.

[PMID:31131842] [INDIRECT EVIDENCE] [SUPPORT] Onpattro, also commonly known as patisiran, is a small interfering RNA (siRNA) molecule packaged within a lipid nanoparticle and is transported into the cell to target transthyretin gene (TTR) messenger mRNA (mRNA) by attaching to its complementary sequence. The target mRNA is degraded and both mutant and wild-type amyloid transthyretin (ATTR) protein production becomes suppressed. --- Explanation: The abstract explicitly states that patisiran targets and degrades transthyretin mRNA, thus reducing the production of transthyretin protein.


MAXO:0000058

[PMID:30561247] [SUPPORT] Inotersen/Tegsedi (Akcea Therapeutics, MA, USA) is a second-generation antisense oligonucleotide (ASO) specific for TTR that inhibits production of TTR by the liver. --- Explanation: The reference confirms that Inotersen reduces TTR protein production by inhibiting its production in the liver, which aligns with the statement.

[PMID:37599395] [SUPPORT] 'Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). --- Explanation: The reference supports that Inotersen is used to treat ATTR amyloidosis and implies its role in reducing TTR protein production.

[PMID:31343345] [SUPPORT] Inotersen treatment for ATTR amyloidosis. --- Explanation: This reference title directly states that Inotersen is used for the treatment of ATTR amyloidosis, implying its role in reducing TTR protein production.


NCIT:C121667

[PMID:30561247] [INDIRECT EVIDENCE] [SUPPORT] Inotersen/Tegsedi (Akcea Therapeutics, MA, USA) is a second-generation antisense oligonucleotide (ASO) specific for TTR that inhibits production of TTR by the liver. --- Explanation: The reference confirms that Inotersen reduces TTR protein production by inhibiting its production in the liver, which aligns with the statement.

[PMID:37599395] [INDIRECT EVIDENCE] [SUPPORT] 'Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). --- Explanation: The reference supports that Inotersen is used to treat ATTR amyloidosis and implies its role in reducing TTR protein production.

[PMID:31343345] [INDIRECT EVIDENCE] [SUPPORT] Inotersen treatment for ATTR amyloidosis. --- Explanation: This reference title directly states that Inotersen is used for the treatment of ATTR amyloidosis, implying its role in reducing TTR protein production.


MAXO:0010039

[PMID:25482846] [SUPPORT] Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. --- Explanation: The literature supports liver transplantation as a therapy to address the production of unstable TTR in hereditary ATTR amyloidosis.

[PMID:23797140] [SUPPORT] Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms. --- Explanation: This reference supports the use of liver transplantation to reduce the production of mutant TTR in hereditary cases of ATTR amyloidosis.


MAXO:0010039

[PMID:32304420] [SUPPORT] However, the end-stage heart failure is common and HTx could be offered to selected patients, especially if affected by light chain cardiac amyloidosis, to allow to perform the autologous stem cell transplantation after the cardiac transplant. --- Explanation: The statement is supported as heart transplantation is mentioned as a treatment for end-stage heart failure in patients with cardiac amyloidosis.

[PMID:33621542] [SUPPORT] Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure. --- Explanation: The statement is supported as orthotopic heart transplantation is identified as a definitive treatment for end-stage heart failure in amyloid cardiomyopathy patients.

[PMID:34922822] [SUPPORT] Heart Transplantation (HT) is a rational therapy for advanced transthyretin cardiac amyloidosis (ATTR-CA)... --- Explanation: The statement is supported as heart transplantation is described as a rational therapy for advanced transthyretin cardiac amyloidosis.


MAXO:0000950

[PMID:33099432] [SUPPORT] Supportive care manages the symptoms of organ involvement and the side effects of treatment. --- Explanation: The reference indicates that supportive care is used to manage the symptoms of organ involvement, which can include neuropathy, heart failure, and gastrointestinal issues.

[PMID:35235819] [PARTIAL] Cardiac amyloidosis (CA) results in symptoms of heart failure, atrial and ventricular arrhythmias, conduction disturbances, and profound autonomic dysfunction. --- Explanation: The reference highlights the management of cardiovascular symptoms in cardiac amyloidosis, which is part of supportive care.

[PMID:35104443] [NO_EVIDENCE] Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues... The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy. --- Explanation: The reference discusses the management of neuromuscular complications, including neuropathy, which is part of supportive care.

[PMID:7588042] [NO_EVIDENCE] The gastrointestinal manifestations of amyloidosis. --- Explanation: The reference discusses gastrointestinal issues related to amyloidosis, which are managed through supportive care.


HGNC.SYMBOL:TTR

[PMID:38844302] [SUPPORT] More than 140 TTR gene variants have been associated with hATTR, with the Val30Met variant representing the most common worldwide. --- Explanation: This reference supports the association of the Val30Met variant with ATTR amyloidosis.

[PMID:24555660] [SUPPORT] A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. --- Explanation: This reference supports the statement about the variable frequency of the Val30Met variant by population.

[PMID:36941075] [SUPPORT] Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation. --- Explanation: This reference supports the statement about the variable frequency of pathogenic variants by population.


HGNC.SYMBOL:APCS


HGNC.SYMBOL:CLU


MONDO:0008702

[PMID:15054848] [SUPPORT] severe micromelia and generalized edema were noted on ultrasound at 21 weeks' gestation --- Explanation: Documents severe micromelia as a key ultrasound finding in ACG2.


MONDO:0008702


MONDO:0008702

[PMID:15054848] [SUPPORT] severe micromelia and generalized edema were noted on ultrasound at 21 weeks' gestation --- Explanation: Documents generalized edema (component of hydrops) as a prenatal finding in ACG2.


MONDO:0008702

[PMID:7829510] [INDIRECT EVIDENCE] [SUPPORT] A transition of G2853 to A in exon 41 produced a substitution of Gly769 by Ser within the triple helical domain of the alpha 1(II) chain of type II collagen, interrupting the mandatory Gly-X-Y triplet sequence required for the normal formation of stable triple helical type II collagen molecules --- Explanation: Demonstrates that glycine substitutions in the Gly-X-Y repeat domain interrupt the formation of stable triple helical collagen molecules.

[PMID:10745044] [INDIRECT EVIDENCE] [SUPPORT] Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S) --- Explanation: Documents multiple glycine substitution mutations in the COL2A1 triple helical domain causing lethal type II collagen disorders.


MONDO:0008702

[PMID:7829510] [INDIRECT EVIDENCE] [SUPPORT] resulting in the complete absence of type II collagen in the cartilage, which had a gelatinous composition --- Explanation: Demonstrates that the COL2A1 mutation results in complete loss of type II collagen from cartilage, leading to abnormal gelatinous matrix composition.

[PMID:7829510] [INDIRECT EVIDENCE] [SUPPORT] Type I and III collagens were the major species found in cartilage tissue and synthesized by cultured chondrocytes along with cartilage type XI collagen --- Explanation: Shows that mutant type II collagen is replaced by type I and III collagens, which are unable to support normal hyaline cartilage structure.

[PMID:10745044] [INDIRECT EVIDENCE] [SUPPORT] Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases --- Explanation: Confirms that abnormal type II collagen processing and replacement by type I collagen is a consistent finding in lethal type II collagenopathies.


hgnc:2200

[PMID:15054848] [SUPPORT] Achondrogenesis type II is a lethal skeletal dysplasia caused by new dominant mutations within the type II collagen gene (COL2A1) --- Explanation: Confirms that ACG2 is caused by dominant mutations in the COL2A1 gene.

[PMID:15054848] [SUPPORT] Molecular analysis of genomic DNA extracted from amniotic cells of the second fetus revealed heterozygosity for a 1340G > A missense mutation (G316D) in the COL2A1 gene --- Explanation: Demonstrates identification of a glycine substitution (G316D) in the COL2A1 gene causing ACG2.

[PMID:10745044] [SUPPORT] Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1) --- Explanation: Confirms that dominant COL2A1 mutations cause achondrogenesis II-hypochondrogenesis.


MONDO:0008702

[PMID:15054848] [SUPPORT] This mutation was not found in the parents. Although, we could not evaluate the presence of this mutation in the first fetus, we strongly believe that our data are in favor of germline mosaicism as the most likely explanation for the recurrence of type II achondrogenesis in both sibs. --- Explanation: Demonstrates that germline mosaicism can cause recurrence of ACG2 within families despite apparent de novo mutations.


MONDO:0007037


MONDO:0007037

[PMID:29959505] [SUPPORT] MRI revealed four severe, four moderate, and one mild case of cervicomedullary compression, and PSG demonstrated severe sleep apnea in four cases and moderate sleep apnea in five cases. --- Explanation: Clinical study showing high prevalence of cervicomedullary compression and sleep apnea secondary to foramen magnum stenosis in achondroplasia, even in patients asymptomatic during daytime.


MONDO:0007037

[PMID:35698202] [SUPPORT] the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. --- Explanation: Expert consensus identifies spinal stenosis as one of the most clinically significant complications of achondroplasia due to high impact on morbidity and quality of life.


MONDO:0007037

[PMID:35028714] [SUPPORT] patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. --- Explanation: Comprehensive review establishing obstructive sleep apnea as a high-prevalence complication in achondroplasia.


MONDO:0007037

[PMID:35028714] [SUPPORT] patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. --- Explanation: Recurrent ear infections are listed among the high-prevalence complications of achondroplasia.


MONDO:0007037

[PMID:35028714] [SUPPORT] patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. --- Explanation: Obesity is documented as a prevalent complication in achondroplasia across the lifespan.


MONDO:0007037

[PMID:35028714] [SUPPORT] patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. --- Explanation: Hydrocephalus is recognized as a complication of achondroplasia, secondary to skull base abnormalities.


MONDO:0007037

[PMID:7913883] [INDIRECT EVIDENCE] [SUPPORT] DNA studies revealed point mutations in the FGFR3 gene in ACH heterozygotes and homozygotes. The mutation on 15 of the 16 ACH-affected chromosomes was the same, a G-->A transition, at nucleotide 1138 of the cDNA. --- Explanation: This landmark 1994 Cell paper by Shiang et al. identified FGFR3 mutations as the cause of achondroplasia, establishing the molecular basis of the disease.

[PMID:7847369] [INDIRECT EVIDENCE] [SUPPORT] All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. --- Explanation: This study of 154 unrelated achondroplasia patients confirmed the G380R mutation is essentially universal, with over 97% having the same recurrent mutation.


MONDO:0007037

[PMID:14871928] [INDIRECT EVIDENCE] [SUPPORT] These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. --- Explanation: Demonstrates that MAPK pathway specifically inhibits chondrocyte differentiation rather than proliferation, with constitutive MEK1 activation recapitulating the achondroplasia phenotype in mice.

[PMID:14871928] [INDIRECT EVIDENCE] [SUPPORT] These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1. --- Explanation: Establishes the dual-pathway model where MAPK inhibits differentiation and STAT1 inhibits proliferation downstream of FGFR3.

[PMID:14751560] [INDIRECT EVIDENCE] [SUPPORT] Our results indicate that FGFR3 mutations in the prenatal period upregulate FGFR3 and Stat-p21Cip1 expression, thus inducing premature exit of proliferative cells from the cell cycle and their differentiation into prehypertrophic chondrocytes. --- Explanation: Human fetal tissue analysis confirms that FGFR3 mutations upregulate STAT/p21 signaling in growth plate chondrocytes, causing premature cell cycle exit and defective differentiation.


MONDO:0007037

[PMID:14751560] [INDIRECT EVIDENCE] [SUPPORT] Immunohistochemical analysis of fetal growth plates showed a phenotype-related reduction of the collagen type X-positive hypertrophic zone. --- Explanation: Direct histological evidence from human fetal growth plates showing reduced hypertrophic zone in achondroplasia, confirming impaired growth plate cartilage development.


MONDO:0007037

[PMID:18923003] [INDIRECT EVIDENCE] [SUPPORT] We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatophoric dysplasia as well as in mouse models of achondroplasia. --- Explanation: Direct evidence that FGFR3 activation causes premature synchondrosis closure in cranial base, demonstrated in both human skeletal dysplasia cases and mouse models.

[PMID:18923003] [INDIRECT EVIDENCE] [SUPPORT] Chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses. --- Explanation: Shows that FGFR3 activation specifically in chondrocytes is sufficient to drive premature synchondrosis closure through a MAPK-dependent mechanism involving enhanced bone formation.

[PMID:14871928] [INDIRECT EVIDENCE] [SUPPORT] Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. --- Explanation: Shows molecular disruption of cranial base chondrocyte maturation upon MAPK activation, consistent with premature closure mechanism.


MONDO:0007037

[PMID:14702637] [INDIRECT EVIDENCE] [SUPPORT] CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. --- Explanation: Demonstrates the mechanism by which CNP counteracts FGFR3 overactivation specifically through MAPK pathway inhibition, establishing the basis for vosoritide therapy.

[PMID:14702637] [INDIRECT EVIDENCE] [SUPPORT] CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. --- Explanation: Shows that CNP selectively inhibits MAPK but not STAT1, explaining why CNP therapy partially but not completely rescues the achondroplasia phenotype.


MAXO:0000058

[PMID:31269546] [SUPPORT] Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. --- Explanation: This NEJM phase 2 trial demonstrated that vosoritide treatment in children with achondroplasia resulted in sustained increases in growth velocity over 42 months of follow-up.

[PMID:39740666] [SUPPORT] The mean (SD) differences in annualized growth velocity across each integer age (6-16 years) between treated and untreated children were 1.84 (0.38) cm/year in boys and 1.44 (0.63) cm/year in girls. --- Explanation: Phase 3 extension study with 119 participants demonstrates that vosoritide provides clinically meaningful growth velocity improvements compared to untreated children across ages 6-16 years.

[PMID:39740666] [SUPPORT] Vosoritide treatment was well tolerated and had sustained growth-promoting effects in children with achondroplasia treated for up to 6 years. --- Explanation: Demonstrates long-term safety and sustained efficacy over 6 years of continuous treatment with a favorable safety profile.


NCIT:C152918

[PMID:31269546] [INDIRECT EVIDENCE] [SUPPORT] Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. --- Explanation: This NEJM phase 2 trial demonstrated that vosoritide treatment in children with achondroplasia resulted in sustained increases in growth velocity over 42 months of follow-up.

[PMID:39740666] [INDIRECT EVIDENCE] [SUPPORT] The mean (SD) differences in annualized growth velocity across each integer age (6-16 years) between treated and untreated children were 1.84 (0.38) cm/year in boys and 1.44 (0.63) cm/year in girls. --- Explanation: Phase 3 extension study with 119 participants demonstrates that vosoritide provides clinically meaningful growth velocity improvements compared to untreated children across ages 6-16 years.

[PMID:39740666] [INDIRECT EVIDENCE] [SUPPORT] Vosoritide treatment was well tolerated and had sustained growth-promoting effects in children with achondroplasia treated for up to 6 years. --- Explanation: Demonstrates long-term safety and sustained efficacy over 6 years of continuous treatment with a favorable safety profile.


MAXO:0000004


MAXO:0000004

[PMID:29959505] [SUPPORT] Three of these patients demonstrated improved sleep respiration soon after surgery, while one required temporary tracheostomy due to bilateral vocal cord paralysis caused by compression during intratracheal intubation. --- Explanation: Clinical evidence showing that cervicomedullary decompression improves sleep-related respiratory disturbance in achondroplasia patients with foramen magnum stenosis.


HGNC.SYMBOL:FGFR3 G380R mutation

[PMID:7847369] [SUPPORT] The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype. --- Explanation: Study of 154 patients showed that 153 had the same G380R mutation, demonstrating the remarkable genetic homogeneity of achondroplasia.


MONDO:0007037

[PMID:8078586] [SUPPORT] Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (10%). --- Explanation: Establishes autosomal dominant inheritance with full penetrance for achondroplasia.

[PMID:8078586] [SUPPORT] More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, --- Explanation: Indicates that most cases are de novo and associated with increased paternal age, supporting a paternal origin effect.


MONDO:0007038

[PMID:31287245] [SUPPORT] Individuals with PSS were more likely to suffer from migraine (odds ratio = 1.97, P = 2.18 × 10-9 ) --- Explanation: Strong statistical association between photic sneeze syndrome and migraine.


MONDO:0007038

[PMID:31287245] [PARTIAL] intolerance to light, commonly known as photophobia, is thought to result from light-induced activation of the trigeminal nerve system --- Explanation: Photophobia and photic sneeze syndrome share trigeminal nerve involvement.


MONDO:0007038

[PMID:31287245] [INDIRECT EVIDENCE] [SUPPORT] The optic‐trigeminal summation hypothesis postulates that, during light stimulation, the activated optic nerve pathways cross‐activate the trigeminal nerve pathways --- Explanation: Cross-activation between visual and trigeminal pathways is a leading hypothesis.

[PMID:39893297] [INDIRECT EVIDENCE] [SUPPORT] Several theories, including optic-trigeminal summation, parasympathetic hypersensitivity, and parasympathetic generalization, have been proposed, but none have been conclusively validated. --- Explanation: 2025 mini-review confirms optic-trigeminal summation remains a leading but unvalidated hypothesis.

[PMID:8536668] [INDIRECT EVIDENCE] [SUPPORT] Neuropharmacological alterations associated with photoperiod mechanisms leading to optic trigeminal summation are suggested as possible reasons for spring onset of headshaking. --- Explanation: Equine photic headshaking provides a natural animal model supporting optic-trigeminal summation. Light-triggered headshaking ceased with blindfolding in 5/5 horses.

[PMID:24107198] [INDIRECT EVIDENCE] [SUPPORT] This study confirms involvement of the trigeminal nerve hyperexcitability in the pathophysiology of disease. --- Explanation: Electrophysiological evidence in horses demonstrates trigeminal nerve hyperexcitability with activation thresholds of 5 mA or less in affected horses versus 10 mA or more in controls, supporting a functional rather than structural basis for light-triggered trigeminal reflexes.


MONDO:0007038


MONDO:0007038

[PMID:31287245] [INDIRECT EVIDENCE] [SUPPORT] According to the parasympathetic generalization hypothesis, when a light stimulus excites a specific branch of the parasympathetic nervous system, it activates other branches, resulting in nasal secretion and a tickling sensation in the nasal mucosa --- Explanation: Parasympathetic generalization is one of the proposed mechanisms.


MONDO:0007038

[PMID:20169159] [INDIRECT EVIDENCE] [SUPPORT] we found a generally enhanced excitability of the visual cortex (mainly in the cuneus) to visual stimuli in 'photic sneezers' compared with control subjects --- Explanation: EEG study demonstrating enhanced visual cortex activation in photic sneezers.

[PMID:20169159] [INDIRECT EVIDENCE] [SUPPORT] a stronger prickling sensation in the nose of photic sneezers was found to be associated with activation in the insula and stronger activation in the secondary somatosensory cortex --- Explanation: Somatosensory cortex co-activation during nasal prickling sensation.


MONDO:0007038

[PMID:27559310] [INDIRECT EVIDENCE] [SUPPORT] melanopsin is expressed in both human and mouse TG neurons --- Explanation: Direct demonstration that trigeminal ganglion neurons express melanopsin, providing an anatomical substrate for retina-independent light detection in the trigeminal system.

[PMID:27559310] [INDIRECT EVIDENCE] [SUPPORT] These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. --- Explanation: Functional electrophysiology confirms melanopsin-expressing trigeminal neurons are intrinsically photosensitive with response properties matching retinal ipRGCs.

[PMID:27559310] [INDIRECT EVIDENCE] [SUPPORT] Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior. --- Explanation: Establishes a light detection pathway entirely independent of the optic nerve that could bypass the retina-to-trigeminal cross-activation route.


MONDO:0007038

[PMID:34133943] [INDIRECT EVIDENCE] [PARTIAL] neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. --- Explanation: NMB-NMBR signaling is the molecular pathway mediating sneeze signal transmission in the brainstem.

[PMID:40415887] [INDIRECT EVIDENCE] [PARTIAL] Current research indicates that the sneeze reflex can be triggered by both internal and external stimuli, including light and temperature. --- Explanation: 2025 review acknowledges light as a trigger of the sneeze reflex but does not establish a direct connection between the NMB pathway and photic sneezing specifically.


MAXO:0000950


HGNC.SYMBOL:rs10427255

[PMID:30899065] [SUPPORT] reproducibly identified both a replicative rs10427255 on 2q22.3 and a novel locus of rs1032507 on 3p12.1 --- Explanation: GWAS-identified risk locus replicated across populations.


HGNC.SYMBOL:rs1032507

[PMID:30899065] [SUPPORT] a novel locus of rs1032507 on 3p12.1 --- Explanation: Novel protective locus near CADM2, which has plausible neurobiological function.


HGNC.SYMBOL:ZEB2

[PMID:30899065] [PARTIAL] rs10427255 was 848 kb downstream of ZEB2 (Zinc Finger E-Box Binding Homeobox 2) --- Explanation: Association is intergenic; ZEB2 involvement is hypothetical.


HGNC.SYMBOL:CADM2

[PMID:30899065] [PARTIAL] the variant of rs1032507 is adjacently upstream of the coding region of CADM2 --- Explanation: Plausible biological candidate but causal role not proven.


HGNC.SYMBOL:NMB

[PMID:34133943] [PARTIAL] neuromedin B (NMB) peptide is essential for signaling sneezing --- Explanation: NMB is the key neuropeptide mediating the sneeze reflex.


HGNC.SYMBOL:NMBR

[PMID:34133943] [PARTIAL] deficiency in NMB receptor abolished the sneezing reflex --- Explanation: NMBR-expressing neurons are essential for the sneeze reflex circuit.


MONDO:0011438

[PMID:24062871] [SUPPORT] evidence has emerged supporting a role for inflammation at all stages of acne lesion development, perhaps subclinically even before comedo formation --- Explanation: This review discusses the role of comedones as a key lesion type in acne pathogenesis.


MONDO:0011438

[PMID:24062871] [SUPPORT] the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule --- Explanation: This review describes the progression from comedones to inflammatory papules in acne lesion development.


MONDO:0011438

[PMID:12113648] [SUPPORT] Localized pustular eruptions are seen on the hands and feet in adults with pustulosis palmaris et plantaris and acrodermatitis continua (both of which may be variants of psoriasis); on the face in patients with acne vulgaris, rosacea, and perioral dermatitis --- Explanation: This review identifies pustular eruptions on the face as a characteristic feature of acne vulgaris.


MONDO:0011438

[PMID:21062102] [SUPPORT] Severe nodular acne, defined as grade 4 or 5 acne on the Investigator's Static Global Assessment scale, is a skin condition characterized by intense erythema, inflammation, nodules, cysts, and scarring. --- Explanation: This review defines severe nodular acne as characterized by nodules and cysts with associated inflammation and scarring potential.


MONDO:0011438

[PMID:34468934] [SUPPORT] the inflammatory processes of acne stimulate excess melanogenesis and abnormal melanin deposition, leading to pigmentary sequelae known as post-inflammatory hyperpigmentation --- Explanation: This paper specifically describes the pathogenesis of acne-induced post-inflammatory hyperpigmentation through excess melanin production.


MONDO:0011438

[PMID:29344322] [SUPPORT] This review focuses on atrophic scars, the most common type of acne scar. --- Explanation: This review confirms atrophic scars as the most common type of acne scarring.


MONDO:0011438

[PMID:32748305] [INDIRECT EVIDENCE] [SUPPORT] Acne pathogenesis is attributed to four key factors: excess sebum production, hyperproliferation of Cutibacterium acnes (C. acnes, formerly called Propionibacterium acnes) bacteria, hyperkeratinization of the pilosebaceous follicles, and inflammatory mechanisms --- Explanation: This review explicitly identifies hyperkeratinization of the pilosebaceous follicles as a key factor in acne pathogenesis.


MONDO:0011438


MONDO:0011438

[PMID:32748305] [INDIRECT EVIDENCE] [SUPPORT] Acne pathogenesis is attributed to four key factors: excess sebum production, hyperproliferation of Cutibacterium acnes (C. acnes, formerly called Propionibacterium acnes) bacteria, hyperkeratinization of the pilosebaceous follicles, and inflammatory mechanisms --- Explanation: Follicular hyperkeratinization is the initiating event that drives microcomedone formation in acne.


MONDO:0011438

[PMID:32748305] [INDIRECT EVIDENCE] [SUPPORT] In acne, mTORC1 mediates sebaceous gland hyperproliferation, lipid synthesis, and hyperplasia of keratinocytes --- Explanation: This review links sebaceous gland hyperproliferation and lipid synthesis to acne pathogenesis.


MONDO:0011438

[PMID:20871834] [INDIRECT EVIDENCE] [SUPPORT] Altered ratio between saturated and unsaturated fatty acids has been indicated as an important feature to be considered in addition to the altered amount of specific fatty acids such as linoleic acid --- Explanation: This review highlights altered sebum fatty acid composition as a pathophysiologic feature of acne.


MONDO:0011438

[PMID:24062871] [INDIRECT EVIDENCE] [SUPPORT] Propionibacterium acnes colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. --- Explanation: This review describes C. acnes colonization and its role in lesion progression.


MONDO:0011438

[DOI:10.3389/fimmu.2023.1075834] [INDIRECT EVIDENCE] [PARTIAL] The inflammasomes are intracellular multimeric protein complexes consisting of an innate immune sensor, the adapter protein ASC and the inflammatory caspases-1 and/or -11 and are important for the host defense against pathogens. --- Explanation: This review explains inflammasome activation, a key mechanism implicated in acne inflammation.


MONDO:0011438

[DOI:10.3389/fimmu.2023.1075834] [INDIRECT EVIDENCE] [PARTIAL] The inflammasomes are intracellular multimeric protein complexes consisting of an innate immune sensor, the adapter protein ASC and the inflammatory caspases-1 and/or -11 and are important for the host defense against pathogens. --- Explanation: Inflammasome activation supports downstream cytokine-mediated inflammation in acne lesions.


MAXO:0000237

[PMID:30674002] [SUPPORT] Topical retinoids are safe and efficacious for the treatment of acne vulgaris. --- Explanation: This systematic review confirms the safety and efficacy of topical retinoids for acne treatment.


MAXO:0000237

[PMID:36927117] [SUPPORT] Large-scale randomized, controlled clinical trials have demonstrated trifarotene to be safe, well tolerated, and efficacious in reducing both comedones and papules/pustules of acne. --- Explanation: This review summarizes randomized trials showing trifarotene efficacy across comedonal and inflammatory acne lesions.


MAXO:0001021

[PMID:19761357] [SUPPORT] BPO-containing combinations do not induce bacterial resistance and are important first-line treatments for mild to moderate acne vulgaris. --- Explanation: This review establishes benzoyl peroxide as an important first-line treatment for acne that does not promote bacterial resistance.


MAXO:0000061

[PMID:16086756] [SUPPORT] topical antibiotics remain one of the cornerstones of acne management --- Explanation: This systematic review confirms topical antibiotics as a cornerstone treatment for acne.


MAXO:0000058

[PMID:41552868] [SUPPORT] At week 24, 67% of participants achieved treatment success, and significant reductions from baseline in inflammatory (88%) and noninflammatory (68%) lesions were observed (p < 0.001, both). --- Explanation: This pooled analysis supports long-term efficacy of the triple-combination gel.


MAXO:0000061

[PMID:28542914] [SUPPORT] isotretinoin therapy reduced acne lesion counts by a clinically relevant amount, and always by a greater amount than control, which was either placebo (two studies), oral antibiotics (seven studies) or other control --- Explanation: This systematic review confirms oral antibiotics as an established comparator treatment for acne in clinical trials.

[PMID:36568833] [SUPPORT] The overuse of topical and/or systemic antibiotics, the long treatment courses used for acne, and the availability of over-the-counter antibiotic preparations, have led to the worldwide emergence of resistant strains in acne patients. --- Explanation: This review documents antibiotic resistance concerns tied to prolonged acne antibiotic use, supporting stewardship in treatment.


MAXO:0000237

[PMID:33085149] [SUPPORT] Oral isotretinoin is the most effective treatment for moderate to severe acne and its side effects are mostly dose-dependent. --- Explanation: This systematic review confirms oral isotretinoin as the most effective treatment for moderate to severe acne.


MAXO:0000283

[PMID:28492054] [SUPPORT] Hormone-based therapies including combined oral contraceptive medications and spironolactone are considered effective therapies to treat adult acne in women. --- Explanation: This systematic review confirms the efficacy of hormonal therapies including oral contraceptives and spironolactone for treating acne in women.


MAXO:0001417

[PMID:37894698] [SUPPORT] The findings of this comprehensive bibliographic review indicate that organic acid-based chemical peels represent effective and safe treatment options for individuals with acne-prone skin. --- Explanation: This review supports organic acid chemical peels as effective and safe adjuncts for acne-prone skin.


MAXO:0001417

[PMID:31455112] [SUPPORT] Peels with 30% AZA reduced acne lesions and normalized the activity of the sebaceous glands. --- Explanation: This study reports acne lesion reduction and sebum normalization with 30% azelaic acid peels.


MAXO:0001417

[PMID:39483653] [SUPPORT] A 30% TCA peel is efficacious and well-tolerated for mild-to-moderate acne scars. --- Explanation: This split-face study supports TCA peels for improving acne scarring.


MAXO:0001578

[PMID:41521693] [SUPPORT] Ablative fractional CO2 laser is effective for acne scar treatment but is often associated with side effects such as erythema and dyspigmentation, along with prolonged recovery time. --- Explanation: This trial background notes efficacy of CO2 laser for acne scars with notable side effects.


MAXO:0000058

[PMID:41521693] [SUPPORT] This study found that CE Ferulic led to enhanced wound healing, reduced erythema and melanin levels, and improved skin hydration following laser treatment, suggesting its beneficial application in combination with laser treatment to accelerate skin recovery. --- Explanation: This split-face trial supports antioxidant serum use after CO2 laser for acne scars.


MAXO:0000014

[PMID:34696155] [SUPPORT] Studies have shown significant improvements in the overall picture of acne. --- Explanation: This systematic review reports clinical improvement in acne with blue light phototherapy.


MAXO:0000014

[PMID:39056372] [SUPPORT] Overall, 92% of patients achieved partial remission of their acne lesions using visible light therapy. --- Explanation: This systematic review summarizes lesion improvement across visible light studies in acne.


MAXO:0000014

[PMID:39226531] [SUPPORT] Newer indications, for which no approval has yet been granted, but which nevertheless have sufficient evidence of efficacy according to the study situation, are inflammatory (lichen sclerosus, acne) and infectious dermatoses (viral warts, cutaneous leishmaniasis, atypical mycobacteriosis). --- Explanation: This review identifies acne as an emerging indication for photodynamic therapy with supportive evidence.


MAXO:0001417

[PMID:35084634] [SUPPORT] The intralesional PRP injection and 1064 nm long-pulsed Nd:YAG laser are safe and effective methods for controlling inflammatory as well as non-inflammatory acne vulgaris in both adolescents and post-adolescent patients. --- Explanation: This randomized split-face study supports Nd:YAG laser and PRP injections for inflammatory acne vulgaris.


MAXO:0001578

[PMID:38271552] [SUPPORT] New 1726 nm lasers specifically target the sebaceous gland, which is known to be pivotal in acne pathophysiology. --- Explanation: This review highlights 1726 nm lasers as a sebaceous gland-targeted treatment approach for acne.


HGNC.SYMBOL:Polygenic susceptibility

[PMID:32748305] [SUPPORT] It is known that multiple factors impact acne pathophysiology, including genetic, hormonal, inflammatory, and environmental influences. --- Explanation: This review explicitly identifies genetic factors as one of the key influences on acne pathophysiology.

[PMID:40689430] [SUPPORT] Both GWAS and single gene disorders unequivocally indicate stem/progenitor cell maintenance and cellular migration as the most important processes in the pathogenesis of acne. --- Explanation: This genetics review connects GWAS and monogenic findings to core biological processes underlying acne susceptibility.


HGNC.SYMBOL:Candidate gene families

[PMID:37662507] [SUPPORT] some genes (such as IL, TNF, RETN, CYP family, MMPs and TIMPs genes et al) are associated with acne vulgaris and may affect the progression and prognosis of the disease. --- Explanation: This review summarizes multiple gene families repeatedly implicated in acne susceptibility and outcomes.


HGNC.SYMBOL:RETN-420C>G and IL6-572G>C polymorphisms

[PMID:35279931] [SUPPORT] There is a strong correlation between RETN-420 and IL6-572 polymorphisms and acne susceptibility; the RETN-420G and IL6-572C alleles increase the risk of acne development. --- Explanation: This study reports RETN-420 and IL6-572 risk alleles associated with acne susceptibility.


HGNC.SYMBOL:TNFR2 M196R and TLR2 Arg753Gln polymorphisms

[PMID:20861605] [SUPPORT] The 196R allele of TNFR2 M196R as well as the 753Gln allele of TLR2 Arg753Gln are risk factors for acne vulgaris in Chinese Han patients, further supporting the contribution of inflammatory cytokines to the pathogenesis of acne. --- Explanation: This study links TNFR2 and TLR2 risk alleles to acne susceptibility in a Chinese Han cohort.


NCBITaxon:1747

[PMID:24062871] [SUPPORT] Propionibacterium acnes colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. --- Explanation: This review links C. acnes colonization to inflammatory progression in acne.


MONDO:0012268

[PMID:1979021] [SUPPORT] The occurrence of unusual infections, in particular Pneumocystis carinii pneumonia... --- Explanation: The reference indicates that Pneumocystis pneumonia is a common phenotype associated with Acquired Immunodeficiency Syndrome (AIDS).

[PMID:33612763] [SUPPORT] Pneumocystis pneumonia (PCP) and pulmonary tuberculosis infection (PTB) are important opportunistic infections in HIV-infected patients. --- Explanation: The reference supports the presence of Pneumocystis pneumonia as a common infection among HIV-infected patients.

[PMID:16182595] [SUPPORT] Pulmonary infection caused by the opportunistic fungal organism Pneumocystis continues to be a leading AIDS defining illness. --- Explanation: The reference supports the statement by indicating that Pneumocystis pneumonia is an important AIDS-defining illness.

[PMID:38110260] [SUPPORT] ...consistent use of Pneumocystis prophylaxis in all HIV exposed/infected children under 5 years of age has considerably reduced associated infections overall and respiratory infections in particular. --- Explanation: The reference suggests that Pneumocystis pneumonia is a common respiratory infection in HIV-infected individuals.

[PMID:7915731] [SUPPORT] The nature of the clinical presentation of HIV infection continues to evolve over time....Pneumocystis carinii pneumonia...can now be added to the classic clinical markers for progressive HIV infection. --- Explanation: The reference supports the statement by listing Pneumocystis pneumonia as a classic clinical marker for HIV infection progression.


MONDO:0012268

[PMID:6496525] [PARTIAL] Candidiasis is, by far, the most common mycotic infection of the human oral cavity... Extensive use of antibiotics and immunosuppressive drugs have greatly increased the number of Candida-induced oral infections. --- Explanation: This reference details multiple forms of candidiasis affecting the mouth, including acute atrophic, chronic atrophic, and chronic mucocutaneous candidiasis, and indicates that it is common.

[PMID:17944709] [SUPPORT] Invasive fungal infections (IFIs) have become a major cause of morbidity and mortality among people with acquired immune deficiency syndrome (AIDS)... Candida albicans accounted for 57.4% of fungal pathogens isolated. --- Explanation: Candidiasis is highlighted as a frequent and significant infection among AIDS patients.

[PMID:2135639] [SUPPORT] Esophageal candidiasis was reported in one fifth of the patients and were reported twice as often in women as in homosexual men. --- Explanation: This study indicates a significant occurrence of esophageal candidiasis among AIDS patients.

[PMID:11363911] [SUPPORT] Candidiasis. --- Explanation: This reference, although brief, provides context for candidiasis as an infectious condition relevant to AIDS.

[PMID:15627906] [SUPPORT] an oral examination was carried out on a group of 200 HIV-infected patients...  ...Of the 86 (54.8%) patients with OC, 48.2% progressed to AIDS... --- Explanation: Candidiasis is cited here in the context of oral candidiasis and its prevalence among HIV-infected patients.


MONDO:0012268

[PMID:2661499] [SUPPORT] One manifestation of this disease is Kaposi's Sarcoma. Usually a rare tumor, it occurs with a high incidence in patients with AIDS. --- Explanation: The abstract confirms that Kaposi's Sarcoma is commonly associated with AIDS, supporting the statement.

[PMID:29660143] [SUPPORT] Kaposi sarcoma is an oligoclonal HHV-8-driven vascular proliferation... We report a 52-year-old Caucasian man with HIV/AIDS and Kaposi sarcoma. --- Explanation: KS is explicitly linked with HIV/AIDS in this case report, supporting the association.

[PMID:7915731] [SUPPORT] New cutaneous (e.g., seborrheic dermatitis, onychomycosis, and tinea pedis) and systemic... markers for progressive HIV infection, such as Kaposi's sarcoma... --- Explanation: Kaposi's sarcoma cited as a marker for AIDS progression supports the statement.

[PMID:35227156] [PARTIAL] Delayed or missed diagnosis of HIV infection leads to a lack of timely therapy, resulting in rapid disease progression with opportunistic infections or malignancies. --- Explanation: Although KS is not explicitly mentioned, malignancies associated with AIDS are noted, supporting the general assertion.

[PMID:9023448] [SUPPORT] These disorders include nodal and extranodal lymphoproliferative lesions... smooth muscle tumors (SMTs), Kaposi's sarcoma... --- Explanation: KS is listed among the reactive and neoplastic proliferative disorders associated with AIDS.