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Cited by 214Genetics and Neurodevelopmental DisordersHereditary Neurological DisordersGenetic Neurodegenerative Diseases

Rett syndrome: a neurological disorder with metabolic components

Open access
Kyle, Stephanie M., Vashi, Neeti, Justice, Monica J.·2018·Open Biology
DOI 10.1098/rsob.170216PMC PMC5830535
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Abstract

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

AI snapshot

Written from the paper’s full text.

TL;DR

Rett syndrome (RTT) is caused by mutations in X-linked MECP2 and has traditionally been treated as a neurological disorder, but this review argues that metabolic dysfunction—especially perturbed lipid and cholesterol metabolism—is an important component. Evidence from Mecp2 mutant mice and patient subsets links MeCP2 to NCoR1/SMRT-HDAC3-mediated repression of lipogenic genes, suggesting lipid markers and statins as potential therapeutic avenues.

Key findings

  • RTT occurs in 1:10,000–15,000 live female births; MECP2 mutations account for 95% of typical RTT cases, and 555 RTT-causing mutations have been identified, with eight common missense/nonsense mutations accounting for approximately 70% of cases, C-terminal deletions approximately 8%, and large deletions approximately 5%.
  • Metabolic complications are common in RTT, including dyslipidaemia, elevated plasma leptin and adiponectin, elevated ammonia, gallbladder inflammation, altered brain carbohydrate metabolism, mitochondrial abnormalities, increased oxidative stress, and elevated lactate/pyruvate; patients also have a sudden unexpected death rate of 26%.
  • A mouse suppressor screen linked MeCP2 to lipid metabolism: a Sqle mutation improved RTT-like motor phenotypes, overall health, and lifespan in Mecp2 null male mice; pre-symptomatic Mecp2 null brains show elevated cholesterol and increased Cyp46a1 expression (38% over wild-type), while post-symptomatic brains show decreased sterol synthesis.
  • MeCP2 bridges methylated DNA to the NCoR1/SMRT-HDAC3 co-repressor complex to repress lipogenic genes; liver-specific Mecp2 deletion causes dyslipidaemia and fatty liver, and fluvastatin or lovastatin improves motor performance and lifespan in 129.Mecp2tm1.1Bird mice, leading to a phase 2 lovastatin trial (NCT02563860).

Methods

  • Narrative review of RTT history, clinical features, MECP2 genetics, animal models, and metabolic evidence; no new primary data are presented.
  • Synthesizes human clinical reports and studies in mouse, rat, zebrafish, and cynomolgus monkey models, including Mecp2 null and point-mutation alleles, conditional deletions, and pharmacological interventions.
  • Main analysis is qualitative integration of cited literature; no systematic search strategy or meta-analysis is described.

Limitations

  • The paper states that metabolic parameters vary greatly within the RTT patient population and among different mouse strains, indicating that genetic variation may play a large role in the penetrance of metabolic symptoms.
  • The paper notes that whole-brain transcriptional profiling studies have not revealed dramatic gene expression changes, perhaps because the heterogeneous brain masks significant perturbations in subpopulations of cells, and definitive gene regulatory targets remain unclear.
  • Evident from the text: as a review, it does not present new experimental data; many mechanistic conclusions rely on mouse models, and human metabolic findings come from subsets of patients, so causality and generalizability to all RTT patients remain uncertain.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1098/rsob.170216

Cites

224 of 224 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

116 of 173 cited sources checked · 54 supported · 1 flagged · accuracy not yet measured

  • Interpretationcitation

    MECP2 mutation status is a strong predictor of disease severity.

    “Therefore, MECP2 mutation status is a strong predictor of disease severity, but phenotype variation commonly occurs between individuals with the same MECP2 mutation and is attributed to differences in X chromosome inactivation (XCI) [97].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [38] Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG 2008 Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome. Neurology 70, 1313– 1321. (doi:10.1212/01.wnl.0000291011.54508.aa) 18337588 PMC2677974 source
    • cites [96] Cuddapah VA et al. 2014 Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J. Med. Genet. 51, 152– 158. (doi:10.1136/jmedgenet-2013-102113) 24399845 PMC4403764 source
  • Premisecitation

    RTT patients have inflammation of the gallbladder.

    “A number of patients present with dyslipidaemia [15,16], elevated plasma leptin and adiponectin [17,18], elevated ammonia [1] and inflammation of the gallbladder, an organ which stores bile for fat digestion [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Freilinger M et al. 2014 Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome. Dev. Med. Child Neurol. 56, 756– 762. (doi:10.1111/dmcn.12358) 24528171 source

      The Methods (Part 1; page unavailable) include cholecystitis—gallbladder inflammation—among the conditions assessed in people with RTT, and the assessment guidelines discuss its presentation and treatment. However, the reported cases in Part 1 are identified as gallstones and/or cholecystectomy; our copy does not specify how many patients, if any, had cholecystitis. The claim is therefore supported as a recognized possible gallbladder condition in RTT, but not as a documented finding in the study's patients. (LLM, conf=0.79)

      Experimental — accuracy not yet measured
  • Premisecitation

    Heterozygous female mice on all genetic backgrounds, as well as female rats, become significantly overweight as they age.

    “Interestingly, heterozygous female mice on all genetic backgrounds, as well as female rats, become significantly overweight as they age [115,117,125], although humans with RTT have a wide range in body mass index [15].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [115] Veeraragavan S et al. 2015 Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome. Hum. Mol. Genet. 25, 3284– 3302. (doi:10.1093/hmg/ddw178) PMC5179927 27365498 source

      The Results comparison of juvenile female rats and mice (Table 1; page unavailable) reports behavioural phenotypes, not body weight. Searches for overweight, body weight, obesity, and age-related weight gain found no passage in our copy establishing that female rats become significantly overweight, or that mice do so on all genetic backgrounds. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [117] Guy J, Hendrich B, Holmes M, Martin JE, Bird A 2001 A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322– 326. (doi:10.1038/85899) 11242117 source

      The body-weight discussion and Fig. 3 (p. 324) report that surviving Mecp2-null males on a C57BL/6×129 background became heavier than littermates. They do not establish weight gain in heterozygous females: the paper says weight effects depend on genetic background and reports underweight mutant mice on a C57BL/6 background. This mouse study provides no evidence about female rats. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [125] Gigli CC, Scaramuzza L, Gandaglia A, Bellini E, Gabaglio M, Parolaro D, Kilstrup-Nielsen C, Landsberger N, Bedogni F 2016 MeCP2 related studies benefit from the use of CD1 as genetic background. PLoS ONE 11, e0153473 (doi:10.1371/journal.pone.0153473) 27097329 PMC4838291 source

      The Results and Discussion (Fig. 4; page not provided) report that CD1 heterozygous female mice became overweight relative to wild-type controls beginning at three months of age. The paper does not establish this for female mice on all genetic backgrounds or for female rats. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    MECP2 mutations commonly occur de novo.

    “It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [36] Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY 1999 Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 23, 185– 188. (doi:10.1038/13810) 10508514 source
    • cites [37] Wan M et al. 1999 Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65, 1520– 1529. (doi:10.1086/302690) 10577905 PMC1288362 source
    • cites [38] Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG 2008 Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome. Neurology 70, 1313– 1321. (doi:10.1212/01.wnl.0000291011.54508.aa) 18337588 PMC2677974 source
  • Premisecitation

    Increased oxidative stress has been observed in RTT patients.

    “Consistently, altered electron transport chain complex function [27], increased oxidative stress [28–30], and elevated levels of lactate and pyruvate in blood and cerebrospinal fluid [20,27] have been observed in RTT patients (reviewed in [31]).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [28] Sierra C, Vilaseca MA, Brandi N, Artuch R, Mira A, Nieto M, Pineda M 2001 Oxidative stress in Rett syndrome. Brain Dev. 23(Suppl 1), S236– S239. (doi:10.1016/S0387-7604(01)00369-2) 11738881 source
    • cites [29] De Felice C et al. 2009 Systemic oxidative stress in classic Rett syndrome. Free Radic. Biol. Med. 47, 440– 448. (doi:10.1016/j.freeradbiomed.2009.05.016) 19464363 source
    • cites [30] Leoncini S, De Felice C, Signorini C, Pecorelli A, Durand T, Valacchi G, Ciccoli L, Hayek J 2011 Oxidative stress in Rett syndrome: natural history, genotype, and variants. Redox Rep. 16, 145– 153. (doi:10.1179/1351000211Y.0000000004) 21888765 PMC6837451 source
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationcitation

    Elevated peripheral lipids may be a biomarker for RTT patients who may respond to statin drugs.

    “Interestingly, lovastatin does not have a strong therapeutic effect on B6.Mecp2tm1.1Bird male mice, supporting the idea that elevated peripheral lipids may be a biomarker for those patients who may respond to statin drugs [188].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [188] Villani C, Sacchetti G, Bagnati R, Passoni A, Fusco F, Carli M, Invernizzi RW 2016 Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice. Elife 5, e22409 (doi:10.7554/eLife.22409) 27892851 PMC5132339 source

      The Discussion argues against using elevated serum cholesterol to identify statin responders: it reports improved motor deficits with fluvastatin in female mice whose serum cholesterol was unchanged. It instead proposes investigating plasma 24S-hydroxycholesterol as a possible biomarker of brain cholesterol metabolism that might help identify patients for treatment; that is not a claim that elevated peripheral lipids predict response. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    MeCP2 may also facilitate transcriptional activation, chromatin compaction and mRNA splicing, while interacting with other regulatory proteins.

    “However, MeCP2 may also facilitate transcriptional activation [77], chromatin compaction [78,79] and mRNA splicing [80,81], while also interacting with a host of other regulatory proteins involved in a variety of molecular pathways [81–84].”
    Quote in the paperNot a substantial claim5 of 5 sources checked
    • cites [77] Chahrour M, Jung SYY, Shaw C, Zhou X, Wong STCTC, Qin J, Zoghbi HYY 2008 MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224– 1229. (doi:10.1126/science.1153252) 18511691 PMC2443785 source
    • cites [78] Georgel PT, Horowitz-Scherer RA, Adkins N, Woodcock CL, Wade PA, Hansen JC 2003 Chromatin compaction by human MeCP2: asssembly of novel secondary chromatin structures in the absence of DNA methylation. J. Biol. Chem. 278, 32 181– 32 188. (doi:10.1074/jbc.M305308200) 12788925 source
    • cites [79] Baker SA, Chen L, Wilkins AD, Yu P, Lichtarge O, Zoghbi HY 2013 An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984– 996. (doi:10.1016/j.cell.2013.01.038) 23452848 PMC3641682 source
    • cites [80] Li R et al. 2016 Misregulation of alternative splicing in a mouse model of Rett syndrome. PLoS Genet. 12, e1006129 (doi:10.1371/journal.pgen.1006129) 27352031 PMC4924826 source
    • cites [81] Young JI et al. 2005 Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc. Natl Acad. Sci. USA 102, 17 551– 17 558. (doi:10.1073/pnas.0507856102) PMC1266160 16251272 source

  • May combine two claims.

    Premisecitation

    MeCP2 represses transcription in a gene-specific manner, interacting with the co-repressor complexes mSIN3A and NCoR1/SMRT.

    “Consistently, MeCP2 represses transcription in a gene-specific manner, interacting with the co-repressor complexes mSIN3A and NCoR1/SMRT [70,76].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [70] Lyst MJ et al. 2013 Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898– 902. (doi:10.1038/nn.3434) 23770565 PMC3786392 source

      The Results (page unavailable) confirm MeCP2’s interactions with both SIN3A and NCoR/SMRT and show repression of a reporter gene. The Discussion (page unavailable) describes silencing of specific genes as a possibility, alongside global inhibition of transcriptional noise; it does not establish gene-specific repression as a general fact. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [76] Nan X, Ng H-HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A 1998 Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386– 389. (doi:10.1038/30764) 9620804 source

  • May combine two claims.

    Premisecitation

    Mecp2 null mice are asymptomatic prior to four weeks of age but have subtle but consistent defects in transcription, ionotropic receptor signalling, and neuronal responsiveness during late embryogenesis and the perinatal period.

    “Though Mecp2 null mice are asymptomatic prior to four weeks of age, there are subtle but consistent defects in transcription, ionotropic receptor signalling, and neuronal responsiveness during late embryogenesis and the perinatal period [122–124].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [122] Bedogni F et al. 2016 Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb. Cortex 26, 2517– 2529. (doi:10.1093/cercor/bhv078) 25979088 source
    • cites [123] Santos M, Silva-Fernandes A, Oliveira P, Sousa N, Maciel P 2007 Evidence for abnormal early development in a mouse model of Rett syndrome. Genes Brain Behav. 6, 277– 286. (doi:10.1111/j.1601-183X.2006.00258.x) 16848781 source

      The Abstract (page unavailable) reports subtle developmental differences from the first postnatal week despite an apparently normal phenotype, and the milestone results describe early reflex deficits in Mecp2-null mice. The paper does not establish defects in ionotropic receptor signalling or neuronal responsiveness, nor does it demonstrate that the reported deficits occurred during late embryogenesis; its transcription discussion does not establish a defect at that stage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [124] Chao H-TT, Zoghbi HYY, Rosenmund C 2007 MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58– 65. (doi:10.1016/j.neuron.2007.08.018) 17920015 PMC2198899 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    MeCP2 may be defined as a transcriptional modulator.

    “Altogether, multiple studies suggest that genes can be activated or repressed by MeCP2, depending upon the cellular context [77,89,90], suggesting that MeCP2 may be defined as a transcriptional modulator.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [77] Chahrour M, Jung SYY, Shaw C, Zhou X, Wong STCTC, Qin J, Zoghbi HYY 2008 MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224– 1229. (doi:10.1126/science.1153252) 18511691 PMC2443785 source
    • cites [89] Ben-Shachar S, Chahrour M, Thaller C, Shaw CA, Zoghbi HY 2009 Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum. Mol. Genet. 18, 2431– 2442. (doi:10.1093/hmg/ddp181) 19369296 PMC2694691 source
    • cites [90] Pacheco NL, Heaven MR, Holt LM, Crossman DK, Boggio KJ, Shaffer SA, Flint DL, Olsen ML 2017 RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome. Mol. Autism 8, 56 (doi:10.1186/s13229-017-0174-4) 29090078 PMC5655833 source

  • May combine two claims.

    Premisecitation

    Cholesterol cannot cross the blood-brain barrier, so any cholesterol the brain requires must be synthesized in situ.

    “Importantly, cholesterol cannot cross the blood–brain barrier (BBB), so any cholesterol that the brain requires must be synthesized in situ [161].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [161] Zlokovic BV 2008 The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178– 201. (doi:10.1016/j.neuron.2008.01.003) 18215617 source

      The Introduction discusses cholesterol in caveolar membranes and BBB transport generally, but does not say whether cholesterol crosses the BBB or whether the brain must synthesize its own. Searches for cholesterol crossing the barrier and synthesis in the brain found no passage addressing either point. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    During the fasting cycle, the NCoR1/SMRT-HDAC3 complex maximally occupies hepatocyte chromatin, repressing expression of genes involved in lipid synthesis and sequestration, and during the feeding cycle it releases chromatin, allowing expression of its targeted loci.

    “During the fasting cycle, the NCoR1/SMRT-HDAC3 complex maximally occupies hepatocyte chromatin, repressing the expression of genes involved in lipid synthesis and sequestration. However, during the feeding cycle, it releases chromatin, allowing for expression of its targeted loci [177].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [177] Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, Liu XS, Lazar MA 2011 A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315– 1319. (doi:10.1126/science.1198125) 21393543 PMC3389392 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Treatment with either fluvastatin or lovastatin improves subjective health scores, motor performance (measured by rotarod and open field activity) and increases lifespan in 129.Mecp2tm1.1Bird male and female mutant mice compared with vehicle controls.

    “Remarkably, treatment with either fluvastatin or lovastatin improves subjective health scores, motor performance (measured by rotarod and open field activity) and increases lifespan in 129.Mecp2tm1.1Bird male and female mutant mice when compared with control mice receiving a vehicle [156].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results section (page unavailable) reports that fluvastatin improved subjective health scores, rotarod performance, open-field activity, and lifespan in male mutant mice versus sham-dosed controls. It reports rotarod and open-field improvements with lovastatin in males, but not improved health scores or lifespan. In females, it reports improved rotarod performance and survival through the fluvastatin trial, but not the full set of outcomes claimed for both drugs and sexes. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisereasoning

    In pre-symptomatic Mecp2 null mice, Cyp46a1 expression is increased, indicating a heightened need for cholesterol turnover.

    “Consequently, the expression of Cyp46a1 is increased, indicating a heightened need for cholesterol turnover.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results section reports that Cyp46a1 expression was 38% higher in P28 Mecp2 null mouse brains and interprets this as indicating a heightened need for neuronal cholesterol turnover. It describes the mice at P28 as displaying mild symptoms, however, not as pre-symptomatic. Page numbers were not supplied. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In symptomatic Mecp2 null mice, triglycerides accumulate in the liver and fatty liver disease develops.

    “Triglycerides accumulate in the liver, and fatty liver disease develops, as indicated by pale liver.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results section reports greatly increased liver triglycerides in symptomatic 129.Mecp2 null males by postnatal day 56, and the Discussion refers to fatty liver disease in these mice. The copy does not report pale liver as the indication of disease, so that detail is unsupported. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sqle is a target of HDAC3, and its transcription increases approximately 170-fold in response to Hdac3 liver deletion.

    “In support of this, Sqle, the suppressor of RTT-like phenotypes in mice, is a target of HDAC3, and its transcription increases approximately 170-fold in response to Hdac3 liver deletion [156,178].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results identify a Sqle mutation that rescues Rett-like phenotypes in mice. The Discussion says Sqle promoter regions appear to be HDAC3 targets in the liver, but our copy does not report an approximately 170-fold increase in Sqle transcription after liver-specific Hdac3 deletion; it also frames the targeting as tentative. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [178] Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW 2008 Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 27, 1017– 1028. (doi:10.1038/emboj.2008.51) 18354499 PMC2323257 source

  • May combine two claims.

    Premisecitation

    Loss of MeCP2 decreases HDAC3 binding to DNA, resulting in hyperacetylated histones, and increases transcription of numerous lipid-regulating genes.

    “Loss of MeCP2 decreases HDAC3 binding to DNA, resulting in hyperacetylated histones, and increases transcription of numerous lipid-regulating genes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [180] Kyle SM, Saha PK, Brown HM, Chan LC, Justice MJ 2016 MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029– 3041. (doi:10.1093/hmg/ddw156) 27288453 PMC5181597 source

  • May combine two claims.

    Premisecitation

    CD1.Mecp2tm1.1Bird mice have an increase in serum triglycerides with no corresponding change in serum cholesterol.

    “Additionally, CD1.Mecp2tm1.1Bird mice have an increase in serum triglycerides with no corresponding change in serum cholesterol [125].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [125] Gigli CC, Scaramuzza L, Gandaglia A, Bellini E, Gabaglio M, Parolaro D, Kilstrup-Nielsen C, Landsberger N, Bedogni F 2016 MeCP2 related studies benefit from the use of CD1 as genetic background. PLoS ONE 11, e0153473 (doi:10.1371/journal.pone.0153473) 27097329 PMC4838291 source

  • May combine two claims.

    Premisecitation

    Restoration of MeCP2 expression in symptomatic Mecp2 mutant mice reversed symptoms, improved neurological assessments and overall health, and 80% of tamoxifen-treated animals survived beyond 30 weeks of age.

    “Remarkably, restoration of MeCP2 expression reversed symptoms: neurological assessments and overall health improved and 80% of TM-treated animals survived beyond 30 weeks of age (end of study).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [145] Guy J, Gan J, Selfridge J, Cobb S, Bird A 2007 Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143– 1147. (doi:10.1126/science.1138389) 17289941 PMC7610836 source

      The passage describing the symptomatic male mice (indexed as Abstract; page unavailable) reports improved symptom scores after MeCP2 restoration and says five of six TM-treated animals survived well beyond the untreated mice’s maximum recorded lifespan of 17 weeks. It does not establish that 80% survived beyond 30 weeks of age or identify 30 weeks as the end of the study. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Conditional deletions of Mecp2 in different subsets of neurons highlight the essential role of MeCP2 in neuronal function, yet their milder presentation suggests additional roles outside the central nervous system.

    “A number of conditional deletions in different subsets of neurons highlight the essential role of MeCP2 in neuronal function, yet their milder presentation suggests additional roles outside the CNS (reviewed in [143]).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [143] Li W 2012 Beyond widespread Mecp2 deletions to model Rett syndrome: conditional spatio-temporal knockout, single-point mutations and transgenic rescue mice. Autism Open Access 2012(Suppl. 1), 5 (doi:10.4172/2165-7890.S1-005) 23946910 PMC3740402 source

      The Specific Spatio-Temporal Deletions section reports that forebrain-neuron Mecp2 deletion produces a milder phenotype and that deletion in other neuronal subsets causes neurological symptoms. It does not infer from those milder phenotypes that MeCP2 has roles outside the CNS. The Widespread Mecp2 Deletions section instead reports that brain-specific deletion in neuronal and glial lineages produces a phenotype similar to widespread deficiency. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisereasoning

    In symptomatic Mecp2 null mice, brain cholesterol remains high but not as high as at younger ages.

    “Owing to decreased synthesis, brain cholesterol remains high, but not as high as at younger ages (smaller red arrow).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results section reports elevated brain cholesterol at P56, when Mecp2 mutant males were severely symptomatic, along with downregulation of cholesterol-biosynthesis genes. But by P70, brain cholesterol in the null mice had returned to wild-type levels; the paper does not support saying it remained high at that later age. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In pre-symptomatic Mecp2 null mice, serum cholesterol is elevated and expression of cholesterol biosynthesis genes is elevated in the liver.

    “Outside of the central nervous system, serum cholesterol is elevated, and expression of cholesterol biosynthesis genes is elevated in the liver.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

      The Results section (‘Mecp2 null males have abnormal cholesterol metabolism’; page unavailable) reports elevated serum cholesterol and liver Hmgcr and Sqle expression in 129.Mecp2 null males at P56, when the mice were severely symptomatic. Liver gene expression was unchanged at P28, and the reported peripheral elevations were not seen in the B6 strain. The paper therefore supports the abnormalities, but not the claim that they occur in pre-symptomatic mice. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Oxysterols can pass lipophilic membranes more easily than cholesterol, allowing for one-way egress across the BBB and into the body.

    “Oxysterols can pass lipophilic membranes more easily than cholesterol, allowing for one-way egress across the BBB and into the body [163].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [163] Lund EG, Guileyardo JM, Russell DW 1999 cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc. Natl Acad. Sci. USA 96, 7238– 7243. (doi:10.1073/pnas.96.13.7238) 10377398 PMC22064 source

      The Discussion (page unavailable) says that 24S-hydroxycholesterol is readily secreted across the blood–brain barrier into circulation and then taken up by the liver. It does not establish that oxysterols generally cross lipophilic membranes more easily than cholesterol, or that passage across the barrier is one-way. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The Sqle mutation improved RTT-like motor phenotypes, overall health and lifespan in Mecp2 null male mice.

    “This mutation in Sqle improved RTT-like motor phenotypes, overall health and lifespan in Mecp2 null male mice [156].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [156] Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013– 1020. (doi:10.1038/ng.2714) 23892605 PMC3837522 source

  • May combine two claims.

    Premisecitation

    Mice with a liver-specific deletion of Hdac3 display increased expression of de novo lipogenesis enzymes due to a constitutively active transcriptional environment, resulting in fatty liver disease and elevated serum cholesterol.

    “Mice with a liver-specific deletion of Hdac3 display an increased expression of de novo lipogenesis enzymes due to a constitutively active transcriptional environment, resulting in fatty liver disease and elevated serum cholesterol [178,179].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [178] Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW 2008 Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 27, 1017– 1028. (doi:10.1038/emboj.2008.51) 18354499 PMC2323257 source
    • cites [179] Sun Z et al. 2012 Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934– 942. (doi:10.1038/nm.2744) 22561686 PMC3411870 source

      The Results sections on Hdac3-depleted fatty liver and metabolic rerouting report that liver-specific Hdac3 deletion increases expression of lipid-synthesis genes and causes hepatosteatosis. The paper describes derepression of lipogenic genes, but does not establish the claimed constitutively active transcriptional environment; no passage found reports elevated serum cholesterol (searched: cholesterol, plasma cholesterol). Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mice with liver-specific deletion of Mecp2 develop dyslipidaemia, fatty liver and metabolic disease.

    “Similar to Mecp2 null mice and a liver-specific deletion of Hdac3, these mice develop dyslipidaemia, fatty liver and metabolic disease.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [180] Kyle SM, Saha PK, Brown HM, Chan LC, Justice MJ 2016 MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029– 3041. (doi:10.1093/hmg/ddw156) 27288453 PMC5181597 source

      The Discussion reports that liver-specific Mecp2 deletion causes fatty liver and increased serum cholesterol, supporting the dyslipidaemia and fatty-liver parts of the claim. But the Introduction says these mice remain insulin sensitive, so the paper does not support a broader claim that they develop metabolic disease such as insulin resistance; it reports insulin resistance in whole-body Mecp2-null mice instead. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Premisecitation

    A dominant nonsense mutation in squalene epoxidase (Sqle) was found in an unbiased forward genetic suppressor screen in Mecp2 null mice.

    “Curiously, a dominant nonsense mutation was found in squalene epoxidase (Sqle), a monooxygenase and rate-limiting cholesterol biosynthesis enzyme, which requires an electron donor from mitochondria for its function [157].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [157] Porter TD 2012 New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology. Acta Pharm. Sin. B 2, 102– 106. (doi:10.1016/j.apsb.2012.02.002) source

      Section 2.2 (page unavailable) identifies squalene monooxygenase as an enzyme in sterol synthesis that requires an electron-transfer partner. It does not report a dominant nonsense mutation, a forward genetic suppressor screen, or findings in Mecp2-null mice. Its discussion of POR and a second microsomal reductase also does not support the citing sentence’s claim that the electron donor comes from mitochondria. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Sqle is a monooxygenase and rate-limiting cholesterol biosynthesis enzyme that requires an electron donor from mitochondria for its function.

    “Curiously, a dominant nonsense mutation was found in squalene epoxidase (Sqle), a monooxygenase and rate-limiting cholesterol biosynthesis enzyme, which requires an electron donor from mitochondria for its function [157].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [157] Porter TD 2012 New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology. Acta Pharm. Sin. B 2, 102– 106. (doi:10.1016/j.apsb.2012.02.002) source

      Section 2.2 identifies Sqle as squalene monooxygenase, an enzyme in sterol synthesis that requires an electron-transfer partner. It describes POR and a second, unidentified microsomal reductase—not an electron donor from mitochondria—and does not call Sqle rate-limiting. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    To maintain homeostasis, cholesterol can be converted into the oxysterol 24(S)-hydroxycholesterol (24S-OHC) by the neuron-specific enzyme CYP46A1.

    “To maintain homeostasis, cholesterol can be converted into the oxysterol 24(S)-hydroxycholesterol (24S-OHC) by the neuron-specific enzyme CYP46A1 (figure 4a) [162].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [162] Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW 2003 Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J. Biol. Chem. 278, 22 980– 22 988. (doi:10.1074/jbc.M303415200) 12686551 source

      The Abstract states that CYP46A1 converts cholesterol to 24(S)-hydroxycholesterol, and the Discussion links this pathway to maintaining brain cholesterol homeostasis. The paper reports expression in neurons of the adult brain, but also reports low-level expression in the liver and testis, so it does not establish that the enzyme is strictly neuron-specific. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The C57BL/6 J inbred strain and the 129/Sv substrains manage peripheral cholesterol metabolism differently, presumably due to differences in the transport of cholesterol breakdown products.

    “The C57BL/6 J inbred strain and the 129/Sv substrains manage peripheral cholesterol metabolism differently, presumably due to differences in the transport of cholesterol breakdown products [172].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [172] Dietschy JM 2009 Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol. Chem. 390, 287– 293. (doi:10.1515/BC.2009.035) 19166320 PMC3066069 source

      The section on cholesterol flux through tissues outside the central nervous system describes peripheral cholesterol transport in mice generally, but does not compare C57BL/6J with 129/Sv or link strain differences to transport of cholesterol breakdown products. Searches for both strain names and that proposed mechanism found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Some RTT patients have bone abnormalities, severe gastrointestinal problems and biliary tract disorders.

    “Interestingly, some RTT patients have bone abnormalities, severe gastrointestinal problems and biliary tract disorders [174–176].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [174] Shapiro JR et al. 2010 Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations. Pediatr. Res. 68, 446– 451. (doi:10.1203/PDR.0b013e3181f2edd2) 20661168 PMC3074246 source
    • cites [175] Motil KJ et al. 2011 Vitamin D deficiency is prevalent in girls and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 53, 569– 574. (doi:10.1097/MPG.0b013e3182267a66) 21637127 PMC3638258 source

      The Discussion reports low bone mineral density and increased fracture risk in females with Rett syndrome, and the Results report scoliosis in 54% of the cohort. Our copy does not report severe gastrointestinal problems or biliary tract disorders in these patients, so it supports only the bone-abnormalities part of the sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [176] Motil KJ et al. 2012 Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 55, 292– 298. (doi:10.1097/MPG.0b013e31824b6159) 22331013 PMC3393805 source

  • May combine two claims.

    Premisecitation

    Both RTT patients and Mecp2 mutant mice present with metabolic syndrome, oxidative stress, cardiac defects, decreased bone density and urological dysfunction.

    “Additionally, both RTT patients and Mecp2 mutant mice present with metabolic syndrome [15,180], oxidative stress [27,29], cardiac defects [211,212], decreased bone density [174,213] and urological dysfunction [214,215].”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [15] Justice MJ, Buchovecky CM, Kyle SM, Djukic A 2013 A role for metabolism in Rett syndrome pathogenesis: new clinical findings and potential treatment targets. Rare Dis. 1, e27265 (doi:10.4161/rdis.27265) 25003017 PMC3978897 source

      For the metabolic-syndrome portion of the sentence, “Considerations for Other Therapies that May Affect Metabolism in RTT Patients” explicitly describes metabolic-syndrome phenotypes in Mecp2-null mice. “A Subset of Rett Patients Display Dyslipidemia” reports elevated lipids in some RTT patients, but does not establish that RTT patients present with metabolic syndrome. No page numbers are provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [180] Kyle SM, Saha PK, Brown HM, Chan LC, Justice MJ 2016 MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029– 3041. (doi:10.1093/hmg/ddw156) 27288453 PMC5181597 source

      The Introduction and Discussion explicitly describe metabolic syndrome in Mecp2 mutant mice. For RTT patients, the Discussion reports abnormal cholesterol and triglyceride levels and glucose intolerance, but says systemic metabolic involvement remains a possibility requiring further examination; it does not establish that patients present with metabolic syndrome. The other conditions in the citing sentence have separate citations and are not assessed here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [27] Haas RH, Nasirian F, Hua X, Nakano K, Hennessy M 1995 Oxidative metabolism in Rett syndrome. 2. Biochemical and molecular studies. Neuropediatrics 26, 95– 99. (doi:10.1055/s-2007-979735) 7566465 source
    • cites [29] De Felice C et al. 2009 Systemic oxidative stress in classic Rett syndrome. Free Radic. Biol. Med. 47, 440– 448. (doi:10.1016/j.freeradbiomed.2009.05.016) 19464363 source
    • cites [211] Hara M et al. 2015 Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias. Sci. Rep. 5, e11204 (doi:10.1038/srep11204) PMC4466896 26073556 source
    • cites [212] Crosson J et al. 2017 Evaluation of QTc in Rett syndrome: correlation with age, severity, and genotype. Am. J. Med. Genet. 173, 1495– 1501. (doi:10.1002/ajmg.a.38191) 28394409 PMC5444992 source

  • May combine two claims.

    Premisecitation

    RTT patients have increased oxidative burden and abnormal mitochondrial structure.

    “RTT patients have increased oxidative burden and abnormal mitochondrial structure, while RTT animal models have defects in the mitochondrial respiratory chain [23,26,200–202] and oxidative changes in the brain [203].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [23] Eeg-Olofsson O, Al-Zuhair AG, Teebi AS, Al-Essa MM 1988 Abnormal mitochondria in the Rett syndrome. Brain Dev.. 10, 260– 262. (doi:10.1016/S0387-7604(88)80010-X) 3218707 source
    • cites [26] Cardaioli E, Dotti MT, Hayek G, Zappella M, Federico A 1999 Studies on mitochondrial pathogenesis of Rett syndrome: ultrastructural data from skin and muscle biopsies and mutational analysis at mtDNA nucleotides 10463 and 2835. J. Submicrosc. Cytol. Pathol. 31, 301– 304. 10457616
    • cites [200] Kriaucionis S, Paterson A, Curtis J, Guy J, MacLeod N, Bird A 2006 Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol. Cell. Biol. 26, 5033– 5042. (doi:10.1128/MCB.01665-05) 16782889 PMC1489175 source

      The Discussion (page unavailable) reports earlier findings of abnormal mitochondrial structure in biopsies from RTT patients. It does not report increased oxidative burden in RTT patients; its mention of oxidative stress concerns other human disorders. The paper’s own respiratory-chain findings concern a mouse model. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [201] Gold WA, Williamson SL, Kaur S, Hargreaves IP, Land JM, Pelka GJ, Tam PPL, Christodoulou J 2014 Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT): implications for the disease phenotype. Mitochondrion 15, 10– 17. (doi:10.1016/j.mito.2014.02.012) 24613463 source
    • cites [202] Müller M, Can K 2014 Aberrant redox homoeostasis and mitochondrial dysfunction in Rett syndrome. Biochem. Soc. Trans. 42, 959– 964. (doi:10.1042/BST20140071) 25109986 source

  • May combine two claims.

    Premisecitation

    Re-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology.

    “Moreover, deletion of MeCP2 from glial cells induces a RTT-like phenotype, and re-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology [193,194].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [193] Lioy DT et al. 2011 A role for glia in the progression of Rett's syndrome. Nature 475, 497– 500. (doi:10.1038/nature10214) 21716289 PMC3268776 source

      The paper reports that tamoxifen-induced MeCP2 re-expression using hGFAPcreT2 improved RTT-like symptoms and restored the number of apical dendritic branches (passages 2, 3, and 6). However, the rescue mice carried a Mecp2Stop allele, not a true null allele: the paper distinguishes them from Mecp2-/y mice and reports residual MeCP2 expression from the stop locus (passage 8). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [194] Nguyen MVC, Felice CA, Du F, Covey MV, Robinson JK, Mandel G, Ballas N 2013 Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology. J. Neurosci. 33, 18 764– 18 774. (doi:10.1523/JNEUROSCI.2657-13.2013) PMC3841446 24285883 source

      The Introduction reports that re-expressing MeCP2 in astrocytes of RTT mice improves motor activity and behavior. It does not specify GFAP-Cre or report restoration of dendritic morphology; this paper's own rescue experiments instead use NG2Cre to target oligodendrocyte-lineage cells (Results, 'MeCP2 expression is restored specifically...'). (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Six mutations in TBLR1 mapped to the WD40 domain of the protein and disrupted MeCP2-binding.

    “Notably, six of these mutations in TBLR1 mapped to the WD40 domain of the protein and disrupted MeCP2-binding [150].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [150] Kruusvee V, Lyst MJ, Taylor C, Tarnauskaitė Ž, Bird AP, Cook AG 2017 Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc. Natl. Acad. Sci. USA 114, E3243– E3250. (doi:10.1073/pnas.1700731114) 28348241 PMC5402415 source

      The section “Disease-Associated TBLR1 Mutations Block MeCP2 Binding” (page unavailable) identifies six TBLR1 mutations and says all map to the WD40 domain. It demonstrates disrupted MeCP2 binding for two of those mutations, D369E and P444R, but does not establish that all six disrupt binding; the Discussion likewise says “at least two.” (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Treatment of Mecp2 null mice with a PTP1B antagonist extended lifespan, decreased hindlimb clasping and improved motor performance.

    “For example, the treatment of Mecp2 null mice with a protein-tyrosine phosphatase 1B (PTP1B) antagonist that was developed to treat Type II diabetes extended lifespan, decreased hindlimb clasping and improved motor performance [207].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [207] Krishnan N, Krishnan K, Connors CR, Choy MS, Page R, Peti W, Van Aelst L, Shea SD, Tonks NK 2015 PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J. Clin. Invest. 125, 3163– 3177. (doi:10.1172/JCI80323) 26214522 PMC4563751 source

      The Results section, “Inhibition of PTP1B improved survival in Mecp2 -/y mice” (page not provided), reports extended survival in male Mecp2-null mice. The paw-clasping and rotarod passages (“Volume 125 Number 8 August 2015,” page not provided) report those improvements in heterozygous female Mecp2 -/+ mice, not null mice. The cited passages also do not establish that the inhibitor was developed to treat type II diabetes. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Both RTT patients and Mecp2 mutant mice have abnormal responses to glucose tolerance tests, and mutant mice are also insulin-resistant.

    “Not surprisingly, both RTT patients and Mecp2 mutant mice have abnormal responses to glucose tolerance tests, and mutant mice are also insulin-resistant [180,195].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [180] Kyle SM, Saha PK, Brown HM, Chan LC, Justice MJ 2016 MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029– 3041. (doi:10.1093/hmg/ddw156) 27288453 PMC5181597 source
    • cites [195] Cooke DW, Naidu S, Plotnick L, Berkovitz GD 1995 Abnormalities of thyroid function and glucose control in subjects with Rett syndrome. Horm. Res. 43, 273– 278. (doi:10.1159/000184309) 7607612 source

  • May combine two claims.

    Premisecitation

    Trolox, a vitamin E derivative, normalized blood glucose levels, reduced oxidative stress and improved exploratory behaviour in Mecp2 mice.

    “Similarly, Trolox, a vitamin E derivative, normalized blood glucose levels, reduced oxidative stress and improved exploratory behaviour in Mecp2 mice [208].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [208] Janc OA, Hüser MA, Dietrich K, Kempkes B, Menzfeld C, Hülsmann S, Müller M 2016 Systemic radical scavenger treatment of a mouse model of Rett syndrome: merits and limitations of the vitamin E derivative Trolox. Front. Cell. Neurosci. 10, 266 (doi:10.3389/fncel.2016.00266) 27895554 PMC5109403 source

  • May combine two claims.

    Premisecitation

    Wild-type neurons have abnormal dendritic morphology when co-cultured with MeCP2-deficient astrocytes, yet MeCP2-deficient neurons have normal dendritic morphology when co-cultured with wild-type astrocytes.

    “Interestingly, wild-type neurons have abnormal dendritic morphology when co-cultured with MeCP2-deficient astrocytes, yet MeCP2-deficient neurons have normal dendritic morphology when co-cultured with wild-type astrocytes [192].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [192] Ballas N, Lioy DT, Grunseich C, Mandel G 2009 Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat. Neurosci. 12, 311– 317. (doi:10.1038/nn.2275) 19234456 PMC3134296 source

      The Results section (“RTT astrocytes cannot support normal neuronal growth”; page unavailable) reports abnormal dendritic morphology in wild-type neurons co-cultured with MeCP2-deficient astrocytes. The Results section (“RTT ACM cannot support normal neuronal growth”; page unavailable) also reports normal morphology in MeCP2-null neurons exposed to conditioned medium from wild-type astrocytes, but does not establish that result for co-culture with the astrocytes themselves. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Known target genes of the MeCP2-NCoR1/SMRT-HDAC3 complex in the liver include Sqle and other lipogenesis enzymes.

    “Known target genes of the complex in the liver include Sqle and other lipogenesis enzymes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Mecp2 mutant rodents recapitulate many hallmark symptoms of RTT and are the most widely accepted tool to study the disorder.

    “Mecp2 mutant rodents recapitulate many hallmark symptoms of RTT and are the most widely accepted tool to study the disorder.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The mechanism by which MECP2 mutations cause RTT symptoms is largely unknown.

    “Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    At four weeks of age, Mecp2 null mice begin to develop uncoordinated gait, hypoactivity, tremors, hindlimb clasping, and irregular breathing, and these phenotypes progress in severity until death.

    “At four weeks of age, null mice begin to develop uncoordinated gait, hypoactivity, tremors, hindlimb clasping reminiscent of the hand stereotypies seen in RTT patients, and irregular breathing. These phenotypes progress in severity until death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MeCP2 is an abundant nuclear protein that is ubiquitously expressed throughout all human tissues, but is particularly abundant within neurons.

    “MeCP2 is an abundant nuclear protein that was originally identified in a screen for proteins with methyl-DNA-specific binding activity. It is ubiquitously expressed throughout all human tissues, but is particularly abundant within neurons [52,53].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Tate P, Skarnes W, Bird A 1996 The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nat. Genet. 12, 205– 208. (doi:10.1038/ng0296-205) 8563762 source
    • cites [53] Lewis JD et al. 1992 Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA. Cell 69, 905– 914. (doi:10.1016/0092-8674(92)90610-O) 1606614 source

  • May combine two claims.

    Interpretationcitation

    MeCP2 has a role in maintaining neuronal maturation, activity and plasticity.

    “In the central nervous system (CNS), MeCP2 is expressed at low levels prenatally, but progressively increases during neuronal maturation and synaptogenesis reaching its peak in mature, post-migratory neurons, suggesting a role for MeCP2 in maintaining neuronal maturation, activity and plasticity [54–57].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [54] Cohen DRS, Matarazzo V, Palmer AM, Tu Y, Jeon O-H, Pevsner J, Ronnett GV 2003 Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol. Cell. Neurosci. 22, 417– 429. (doi:10.1016/S1044-7431(03)00026-5) 12727440 source
    • cites [55] Jung BP, Jugloff DGM, Zhang G, Logan R, Brown S, Eubanks JH 2003 The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J. Neurobiol. 55, 86– 96. (doi:10.1002/neu.10201) 12605461 source
    • cites [56] Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM 2004 Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum. Mol. Genet. 13, 629– 639. (doi:10.1093/hmg/ddh063) 14734626 source
    • cites [57] Kishi N, Macklis JD 2005 Dissecting MECP2 function in the central nervous system. J. Child Neurol. 20, 753– 759. (doi:10.1177/08830738050200091001) 16225831 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Targets of the MeCP2-NCoR1/SMRT-HDAC3 complex in the brain remain unknown.

    “Targets in the brain remain unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Metabolic parameters vary greatly within the RTT patient population and among different mouse strains, indicating that genetic variation may play a large role in the penetrance of metabolic symptoms.

    “Despite this, metabolic parameters vary greatly within the RTT patient population and among different mouse strains indicating that genetic variation may play a large role in the penetrance of metabolic symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    RTT patients show abnormal neuronal morphology, but not neuronal death.

    “RTT patients show abnormal neuronal morphology, but not neuronal death, giving legitimacy to the possibility that defective MeCP2-deficient cells can recover [144].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Armstrong D, Dunn JK, Antalffy B, Trivedi R 1995 Selective dendritic alterations in the cortex of Rett syndrome. J. Neuropathol. Exp. Neurol. 54, 195– 201. (doi:10.1097/00005072-199503000-00006) 7876888 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Statins competitively inhibit HMGCR, a rate-limiting step in cholesterol biosynthesis, effectively reducing endogenous production of cholesterol.

    “The primary mechanism of action for statin drugs is to competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting step in cholesterol biosynthesis [181], effectively reducing the endogenous production of cholesterol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Istvan ES, Deisenhofer J 2001 Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160– 1164. (doi:10.1126/science.1059344) 11349148 source

  • May combine two claims.

    Premisecitation

    Newborn neurons must produce cholesterol in a cell-autonomous manner, but as they mature they outsource production to astrocytes.

    “As cholesterol synthesis is a resource-expensive process, current data suggest that newborn neurons must produce cholesterol in a cell-autonomous manner, but as they mature they outsource production to astrocytes (reviewed in [160,191]).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [160] Pfrieger FW, Ungerer N 2011 Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357– 371. (doi:10.1016/j.plipres.2011.06.002) 21741992 source
    • cites [191] Pfrieger FW 2003 Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 25, 72– 78. (doi:10.1002/bies.10195) 12508285 source

  • May combine two claims.

    Interpretationreasoning

    Peripheral deficiency of MeCP2 must be considered as CNS-targeted gene therapy becomes realistic because these symptoms are likely to persist following targeted genetic treatment to the brain.

    “As CNS-targeted gene therapy becomes a more realistic therapeutic approach, peripheral deficiency of MeCP2 must be considered more than ever as these symptoms are likely to persist following targeted genetic treatment to the brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    No single treatment has yet fixed every phenotype in Mecp2 mice or yet proved to effectively treat RTT symptoms.

    “However, despite this progress, no single treatment has yet fixed every phenotype in Mecp2 mice or yet proved to effectively treat RTT symptoms.”
    Quote in the paperSubstantial claim
47 of 47

  • The paper relies on this without support.

    Treatment options for RTT patients are currently limited and centred on symptom relief.

    “Consequently, treatment options for patients are currently limited and centred on symptom relief.”

  • The paper relies on this without support.

    Dietary and drug intervention can alter lipid metabolism.

    “Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism.”

  • The paper relies on this without support.

    RTT research has focused on the role of MECP2 in the central nervous system.

    “Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system.”

  • The paper relies on this without support.

    RTT has been thought to be an entirely neurological disorder.

    “Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system.”

  • The paper relies on this without support.

    Lipid anomalies had never before been described in RTT, and whether cholesterol played a primary role in the pathology of RTT was unknown.

    “However, lipid anomalies had never before been described in RTT and whether cholesterol played a primary role in the pathology of the disease was unknown.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Exon deletions listed as point-mutation alleles

    Minor

    Table 3 places alleles described as deletions of exon 1 or exon 2 under its "point mutation alleles" heading. The paper elsewhere distinguishes point mutations from deletions as separate mutation types.

1 of 1

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Authors
Kyle, S. M., Vashi, N., & Justice, M. J.
Affiliations
  • Baylor College of Medicine (US)
  • University of Toronto (CA)
Corresponding author
Justice, Monica J.
ORCID
Venue
Open Biology
Publisher
The Royal Society
Published
2018-02
Volume
8
Issue
2
ISSN
2046-2441 (ISSN-L)
DOI
10.1098/rsob.170216
PMC
PMC5830535
OpenAlex
W2787504356
Cited by
213
References
224
Citations by year
2026: 15 · 2025: 34 · 2024: 40 · 2023: 36 · 2022: 23 · 2021: 23 · 2020: 22 · 2019: 16 · 2018: 3
FWCI
8.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Open Biology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Angel Ava Fund
  • Rett Syndrome Research Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
Rett syndrome, MeCP2, X-linked disorders, lipid metabolism, metabolic dysfunction, dietary intervention, pharmacological interventions, transcriptional regulation
MeSH terms
Animals, Brain, Disease Models, Animal, Female, Humans, Lovastatin, Mutation, Quality of Life, Rett Syndrome, Disease Progression, History, 20th Century, Lipid Metabolism, Mice, Methyl-CpG-Binding Protein 2, Drug Repositioning

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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