Rett syndrome: a neurological disorder with metabolic components

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The paper’s Abstract explicitly calls MECP2 mutation type a strong predictor of disease severity in Rett syndrome. The Discussion likewise reports a strong association between mutation type and phenotype in typical and atypical Rett syndrome. (LLM, conf=0.94)

  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

In the paper

“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].”

What the sources say

• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Could not verify

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

“It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The Abstract reports de novo missense mutations and says that the high proportion of sporadic RTT cases requires a high rate of new mutations. The Discussion also describes independent de novo recurrences of MECP2 mutations, supporting the claim that they commonly arise de novo. (LLM, conf=0.92)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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]).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  The paper’s “OS markers and MeCP2 gene mutations” section reports significantly increased oxidative-stress markers in RTT patients compared with controls. Its table of RTT clinical presentations also describes increases across several RTT forms. The cited claim is limited to increased oxidative stress; it does not attribute the sentence’s other findings to this source. (LLM, conf=0.94)

  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

In the paper

“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.”

• Also stated in: § Mutations in MECP2 cause Rett syndrome · boosted

  “It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The Abstract identifies Rett syndrome as a neurodevelopmental disorder and MECP2 as the responsible gene. The Discussion states that mutations in MECP2 cause RTT, and the paper identifies MECP2 as X-linked. (LLM, conf=0.94)

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Curiously, body weight in Mecp2 null mice differs depending on genetic background; male Mecp2tm1.1Bird/Y mice on a C57BL/6J background are substantially underweight by four weeks of age compared with wild-type littermates.”

What the sources say

• Supported

  The phenotype discussion states that body weight in Mecp2-null mice depended on genetic background. It reports that mutants on a C57BL/6 background were substantially underweight from four weeks, whereas mice crossed to a 129 strain showed a different weight pattern; the Fig. 3 legend also compares mutant males with wild-type littermates. (LLM, conf=0.94)

  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
• Supported

  The Results and Discussion (Fig. 4A; page not provided) directly compare body weight across genetic backgrounds: CD1 Mecp2-null mice are moderately underweight at P35 and later reach wild-type weight, whereas B6 null mice are strongly underweight from birth. This supports the attributed claim that body weight in Mecp2-null mice differs by genetic background. (LLM, conf=0.94)

  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

In the paper

“Metabolic complications are also common in RTT.”

What the sources say

• Supported

  The section “A Subset of Rett Patients Display Dyslipidemia” reports that pediatric RTT patients commonly had elevated cholesterol, triglycerides, or LDL. At least one of these lipid measures was elevated in 52%, 44%, and 30% of the three age groups studied. The authors note that these retrospective findings are preliminary. (LLM, conf=0.92)

  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
• Partly supported

  The Results and Discussion report significantly higher total and LDL cholesterol in the studied RTT patients than in healthy controls, supporting a specific metabolic alteration. The paper does not establish how common metabolic complications are across people with RTT, or address metabolic complications broadly. (LLM, conf=0.82)

  cites [16] Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, Pallottini V 2014 Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE 9, e104834 (doi:10.1371/journal.pone.0104834) 25118178 PMC4130597 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [17] Acampa M, Guideri F, Hayek J, Blardi P, De Lalla A, Zappella M, Auteri A 2008 Sympathetic overactivity and plasma leptin levels in Rett syndrome. Neurosci. Lett. 432, 69– 72. (doi:10.1016/j.neulet.2007.12.030) 18226448 source
• ?Not checked — no full text of the sourcecites [18] Blardi P, De Lalla A, D'Ambrogio T, Vonella G, Ceccatelli L, Auteri A, Hayek J 2009 Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin. Endocrinol. 70, 706– 709. (doi:10.1111/j.1365-2265.2008.03386.x) 18710461 source
• ?Could not verify

  The Introduction reports that gastrointestinal problems are common in RTT, but does not establish that metabolic complications are common. The Discussion mentions abnormal cholesterol metabolism in Mecp2-mutant mice and describes gallbladder disease in RTT as infrequent; neither establishes the claimed prevalence of metabolic complications in people with RTT. (LLM, conf=0.76)

  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 sourceExperimental — accuracy not yet measured

In the paper

“It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo [36–38].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  The Discussion (Mutation Detection) reports that MECP2 mutations were detected in approximately 50% of patients with RTT, not 95% of typical cases. It also says screening covered only the coding region, so that detection rate does not establish a contrary overall rate. The Abstract supports the link between MECP2 mutations and RTT, but not the claimed 95% figure. (LLM, conf=0.87)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• Supported

  The section “A Subset of Rett Patients Display Dyslipidemia” reports elevated cholesterol, triglycerides, or LDL in some of the 84 female RTT patients whose lipid panels were analyzed. It explicitly characterizes these findings as dyslipidemia, while noting that the retrospective data are preliminary. (LLM, conf=0.94)

  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
• Supported

  The Results and Discussion report significantly higher total cholesterol and LDL-cholesterol in the 15 RTT patients than in healthy controls. This directly supports the claim that some RTT patients present with dyslipidaemia; the paper does not report a prevalence for RTT patients generally. (LLM, conf=0.93)

  cites [16] Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, Pallottini V 2014 Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE 9, e104834 (doi:10.1371/journal.pone.0104834) 25118178 PMC4130597 source

In the paper

“XCI can be skewed preferentially so the mutant X chromosome is more or less expressed than the wild type, resulting in either a relatively more severe or milder presentation of RTT, respectively [98,99].”

What the sources say

• Partly supported

  The Introduction and Results (section 3.2) link greater activity of the paternal X chromosome with a more severe phenotype in one of two twins. The Discussion (section 4) proposes that suppressing a mutated paternal allele might produce a milder phenotype, but treats the mutation’s paternal origin and that mechanism as possibilities, not established causes. It also reports that the sisters differed in severity without a significant difference in X-inactivation pattern. (LLM, conf=0.86)

  cites [98] Ishii T, Makita Y, Ogawa A, Amamiya S, Yamamoto M, Miyamoto A, Oki J 2001 The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome. Brain Dev. 23(Suppl. 1), S161– S164. (doi:10.1016/S0387-7604(01)00344-8) 11738865 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [99] Hoffbuhr KC, Moses LM, Jerdonek MA, Naidu S, Hoffman EP 2002 Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype. Ment. Retard. Dev. Disabil. Res. Rev. 8, 99– 105. (doi:10.1002/mrdd.10026) 12112735 source

In the paper

“Remarkably, five of the seven MeCP2 protein interactors identified were subunits of the NCoR1/SMRT co-repressor complex [70].”

What the sources say

• Supported

  The Results state that five of the top seven proteins identified after purifying MeCP2 from mouse brains were subunits of the NCoR/SMRT co-repressor complexes. This directly supports the citing sentence, with the source’s qualification that these were the top seven identified proteins. (LLM, conf=0.94)

  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

In the paper

“In a landmark study, Guy et al. achieved symptom reversal in Mecp2 mutant mice following the onset of motor dysfunction and neurological deficits.”

What the sources say

• Supported

  The paper reports that five of six symptomatic Mecp2 mutant male mice were rescued after treatment, with improvement in scored symptoms including gait and hindlimb clasping (passage 3, section labeled Abstract; page not provided). It also states that late-onset neurological symptoms in mature adult mutant females were reversible (passage 4, same section). (LLM, conf=0.94)

  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

In the paper

“Pre-symptomatically, Mecp2 null whole brain cholesterol is elevated, and Cyp46a1 expression is increased 38% over wild-type levels, indicating a heightened need for cholesterol turnover in neurons [156] (figure 4b).”

What the sources say

• Partly supported

  The Results section reports a 38% increase in Cyp46a1 expression at P28 and interprets it as a heightened need for neuronal cholesterol turnover. It reports elevated brain cholesterol at P56, when the mice were severely symptomatic—not pre-symptomatically. The Online Methods section also specifies that brain analyses used the subcortical region, rather than the whole brain. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Nevertheless, these findings support the idea that lipid metabolism, a pathway that has many opportunities for drug or dietary intervention, could be exploited for symptom improvement in a subset of RTT patients [156].”

What the sources say

• Supported

  The Discussion states that the mouse findings suggest a subset of RTT patients may benefit from pharmacological interventions that modulate lipid metabolism. It presents symptom improvement in patients as a possibility, not an established clinical result, matching the claim’s cautious wording. (LLM, conf=0.92)

  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

In the paper

“This suggests that a very important role of MeCP2 is to link DNA to the NCoR1/SMRT complex.”

What the sources say

• Supported

  The paper states that its findings support a model in which MeCP2’s predominant function is to recruit the NCoR/SMRT complex to methylated chromatin (passage 3). It also reports that truncated MeCP2 proteins bridged DNA with a subunit of that complex in cell assays (passage 2). This supports the citing sentence’s suggested important role. (LLM, conf=0.94)

  cites [155] Tillotson R, Selfridge J, Koerner MV, Gadalla KKE, Guy J, De Sousa D, Hector RD, Cobb SR, Bird A 2017 Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature 550, 398– 401. (doi:10.1038/nature24058) 29019980 PMC5884422 source

In the paper

“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].”

What the sources say

• Supported

  The Methods (Mice breeding and genotyping) identify the experimental mice as male B6.Mecp2tm1.1Bird/y mice. The Results (Rotarod and hanging-wire test) report no effect of lovastatin on their hanging-wire performance, and the Discussion says its reported motor benefit could not be confirmed on the B6 background. The statement about a possible lipid biomarker is the citing authors’ inference, not part of the treatment-effect claim attributed to this source. (LLM, conf=0.93)

  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

In the paper

“Indeed, Kyle et al. [180] showed that Mecp2 mutant mice develop severe dyslipidaemia due to aberrant transcription of lipogenesis enzymes in the liver, because MeCP2 interacts with the NCoR1/SMRT-HDAC3 complex to repress lipogenic gene transcription.”

What the sources say

• Supported

  The Results section reports increased hepatic lipogenic-enzyme expression and lipid accumulation in Mecp2-null mice. The Discussion explicitly says that loss of liver MeCP2 causes aberrant lipogenesis leading to dyslipidaemia, while the Results show MeCP2 associating with the NCoR1–HDAC3 corepressor complex in liver. Page numbers were not available in our copy. (LLM, conf=0.92)

  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

In the paper

“These findings have led to a model wherein MeCP2 serves as a bridge between methylated DNA and the corepressor complex, anchoring the NCoR1/SMRT complex to DNA via its NID and MBD, respectively.”

What the sources say

• Supported

  The Results identify the NID as MeCP2’s NCoR/SMRT interaction domain and show that an MBD mutation disrupts localization to methylated DNA while preserving NCoR/SMRT binding. The Results also conclude that MeCP2 can recruit NCoR/SMRT to methylated DNA in vivo, supporting the proposed bridging model. (LLM, conf=0.94)

  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
• Supported

  The main text describes a DNA-binding domain required for MeCP2 binding to methylated DNA and identifies the repressor-domain region around T308 as a binding site for the NCoR complex. Together, these passages support the proposed bridge model; the paper does not need to use the words “bridge,” “NID,” or “MBD” to support the paraphrase. (LLM, conf=0.85)

  cites [71] Ebert DH et al. 2013 Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341– 345. (doi:10.1038/nature12348) 23770587 PMC3922283 source

In the paper

“Even so, treatment with either statin improves cholesterol homeostasis in the brains of Mecp2 mutant mice, lowers serum cholesterol and ameliorates lipid accumulation in the liver.”

What the sources say

• Partly supported

  The Results section reports that statin treatment ameliorated liver lipid accumulation in male Mecp2 mutant mice and specifically identifies fluvastatin as reducing it to wild-type levels in female mutants (Fig. 5e; Fig. 6d,e; page unavailable). It reports improved motor symptoms with lovastatin, but does not establish that lovastatin also reduced liver lipid accumulation. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Even so, treatment with either statin improves cholesterol homeostasis in the brains of Mecp2 mutant mice, lowers serum cholesterol and ameliorates lipid accumulation in the liver.”

What the sources say

• Partly supported

  The Results section reports that fluvastatin moved cholesterol intermediates in Mecp2 mutant mouse brains toward wild-type levels. It reports improved motor symptoms with lovastatin, but does not establish that lovastatin improved brain cholesterol homeostasis. The Results also report reduced serum cholesterol and liver lipid accumulation with statin treatment; those findings do not establish the brain effect for both drugs. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured

In the paper

“In 2001, Kokura et al. [83] first demonstrated that MeCP2 binds to the NCoR1/SMRT co-repressor complex.”

What the sources say

• Partly supported

  The binding-results section reports that purified MeCP2 binds directly to an N-CoR fragment. The Discussion describes the N-CoR/SMRT complex but says only that separate co-repressor complexes may associate with MeCP2; it does not demonstrate binding to the intact N-CoR/SMRT complex or to SMRT. (LLM, conf=0.88)

  cites [83] Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S 2001 The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276, 34 115– 34 121. (doi:10.1074/jbc.M105747200) 11441023 sourceExperimental — accuracy not yet measured

In the paper

“Pre-symptomatically, Mecp2 null whole brain cholesterol is elevated, and Cyp46a1 expression is increased 38% over wild-type levels, indicating a heightened need for cholesterol turnover in neurons [156] (figure 4b).”

What the sources say

• Partly supported

  The Results section (“Mecp2 null males have abnormal cholesterol metabolism”) reports that Cyp46a1 expression was 38% above wild type at P28, but says the mice already displayed mild symptoms then—not that they were pre-symptomatic. It reports higher brain cholesterol at P56, a later time point when the mice were severely symptomatic. (LLM, conf=0.92)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Even so, treatment with either statin improves cholesterol homeostasis in the brains of Mecp2 mutant mice, lowers serum cholesterol and ameliorates lipid accumulation in the liver.”

What the sources say

• Partly supported

  The Results section reports that fluvastatin lowered serum cholesterol in male Mecp2 mutant mice. It also reports lovastatin treatment, but describes improved motor symptoms rather than a serum-cholesterol result for that drug. The general statement that statin treatment decreased serum cholesterol does not establish the claimed effect for each statin separately; the same section also reports unchanged serum cholesterol in fluvastatin-treated female mutants. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Biochemistry studies have largely failed to find definitive gene regulatory targets, in part, because MeCP2 binds DNA at levels rivalling histone octamers [190].”

What the sources say

• Supported

  The Results section ('MeCP2 is enriched in neuronal nuclei and almost as abundant as nucleosomes'; page not supplied) reports that the number of MeCP2 molecules in mature neuronal nuclei approaches the number of histone octamers. The Results also report genome-wide MeCP2 binding, supporting the paraphrase about DNA binding at comparable levels. (LLM, conf=0.90)

  cites [190] Skene PJ, Illingworth RS, Webb S, Kerr ARW, James KD, Turner DJ, Andrews R, Bird AP 2010 Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457– 468. (doi:10.1016/j.molcel.2010.01.030) 20188665 PMC4338610 source

In the paper

“While both 129.Mecp2tm1.1Bird mice and B6.Mecp2tm1.1Jae mice show decreased sterol synthesis in the brain, elevated cholesterol and triglycerides in the serum and liver are observed only in 129.Mecp2tm1.1Bird mice [156].”

What the sources say

• Partly supported

  In Results, under “Mecp2 null males have abnormal cholesterol metabolism” (page not provided), the paper reports significantly elevated serum cholesterol and triglycerides in 129.Mecp2tm1.1Bird/Y mice, but not B6.Mecp2tm1.1Jae/Y mice at P56. It also reports increased liver triglycerides in Bird mice, but says total liver cholesterol was unchanged and liver triglycerides increased modestly in Jae mice. Thus, the claim is not supported for elevated liver cholesterol or for liver triglycerides occurring only in Bird mice. (LLM, conf=0.91)

  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 sourceExperimental — accuracy not yet measured

In the paper

“While both Ncor1 and Hdac3 null mice die as embryos, a neuron-specific deletion of Hdac3 produces viable mice that gradually develop a phenotype very similar to that of Mecp2 null mice including abnormal motor coordination, reduced sociability and cognitive defects [189].”

What the sources say

• Partly supported

  The Results sections on locomotor behavior and social and cognitive deficits report viable forebrain-neuron Hdac3 conditional knockout mice with impaired motor coordination, aberrant sociability, and memory deficits. The Discussion says these behaviors resemble those in Mecp2 loss-of-function models. The paper does not establish that the deficits developed gradually, and its comparison is to Mecp2 loss-of-function models, particularly forebrain-specific knockouts, rather than specifically to Mecp2 null mice. (LLM, conf=0.87)

  cites [189] Nott A et al. 2016 Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat. Neurosci. 19, 1497– 1505. (doi:10.1038/nn.4347) 27428650 PMC5083138 sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, liver-specific deletion of Mecp2 (B6.Mecp2tm1Bird/Y;Alb-Cre) also results in an increase in lipogenic enzyme transcription [180].”

What the sources say

• Supported

  The Results section, “A conditional deletion of Mecp2 from mouse liver dissociates fatty liver and insulin resistance,” describes the B6.Mecp2flox/Y;Alb-Cre liver-specific deletion and states that hepatocyte deletion increases transcription of lipogenesis-pathway genes, including Hmgcr, Sqle, Scd1, and Fasn (Fig. 5C). (LLM, conf=0.94)

  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

In the paper

“These results support a hepatocyte-autonomous role for Mecp2 in co-ordinating repression of enzymes of the cholesterol and triglyceride biosynthesis pathways and show that loss of Mecp2 from the liver is sufficient to cause metabolic disease in mice.”

What the sources say

• Supported

  The Results section reports that liver-specific Mecp2 deletion causes fatty liver and increased serum cholesterol in mice. The Discussion identifies these effects as dyslipidemia and non-alcoholic fatty liver disease. The paper also notes that the liver-specific deletion does not cause insulin resistance, but the claim does not attribute that outcome to it. (LLM, conf=0.93)

  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

In the paper

“This binding oscillation governs the switch between lipid and glucose utilization in hepatocytes.”

What the sources say

• Partly supported

  The passages labeled Abstract (page not supplied) report that HDAC3 binding oscillates in mouse liver and regulates a daily cycle of lipid synthesis and accumulation. They do not show that this oscillation governs a switch between lipid and glucose utilization in hepatocytes; the mention of glucose metabolism does not establish such a switch. (LLM, conf=0.86)

  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 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Supported

  The Figure 1 caption in “Implications for Patients and Relevance to Statin Treatment” states that RTT patients’ BMI ranged from below the 5th to the 95th percentile. The “RTT Patients” section also notes that some patients have high BMI while many are at the extreme low end. (LLM, conf=0.94)

  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

In the paper

“In symptomatic Mecp2 null mice (8–10 weeks old), the brain is smaller due to lack of Mecp2. Cholesterol biosynthesis decreases drastically in the brain, likely due to feedback from elevated 24S-OHC.”

What the sources say

• Partly supported

  The Results section reports decreased brain cholesterol synthesis in severely symptomatic Mecp2 mutant males at P56, and the Discussion quantifies a 23% decrease per gram of brain tissue in null mice. The paper suggests that excess brain cholesterol feeds back to reduce synthesis; it does not attribute that feedback to elevated 24S-OHC. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (§2.2; page not provided) report lower brain cholesterol synthesis in Mecp2-null mice at 21–56 days, including 56 days (8 weeks). But the Discussion (§3) calls the effect modest, not drastic, and says the signal is unknown; it proposes investigating 24S-OHC rather than finding elevated levels or feedback from them. This study did not test mice at 10 weeks. (LLM, conf=0.90)

  cites [171] Lopez AM, Chuang J-C, Posey KS, Turley SD 2017 Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis. Brain Res. 1654A, 77– 84. (doi:10.1016/j.brainres.2016.10.021) PMC5131633 27789278 sourceExperimental — accuracy not yet measured

In the paper

“In pre-symptomatic Mecp2 null mice (3–4 weeks old), increased expression of cholesterol biosynthesis genes in the brain leads to elevated brain cholesterol levels.”

What the sources say

• Partly supported

  The Results section (“Mecp2 null males have abnormal cholesterol metabolism”; page unavailable) reports increased brain expression of Cyp46a1, a cholesterol-turnover gene, at P28, when the mice already had mild symptoms. It reports higher brain cholesterol at P56, not at 3–4 weeks. The passage therefore does not establish that increased biosynthesis-gene expression led to elevated brain cholesterol in pre-symptomatic mice. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, this group found that the interaction between MeCP2 and the NCoR1/SMRT complex was facilitated by the NCoR1/SMRT interaction domain (NID) located at MeCP2 amino acids 285–309 [70,71].”

What the sources say

• Partly supported

  The Results identify a MeCP2 NCoR/SMRT interaction domain and report that residues 269–309 were necessary for binding in deletion experiments. They also report direct binding by a peptide spanning residues 285–319. The claimed boundary of 285–309 is not established by either result. (LLM, conf=0.87)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The main text reports that the region of MeCP2 surrounding T308 specifically mediates binding to the NCoR complex. However, the Methods (Peptide pull-down assays; page unavailable) identify the tested peptide as amino acids 285–319, not 285–309, and the cited passages do not establish 285–309 as the domain's boundaries or specifically name the SMRT complex. (LLM, conf=0.88)

  cites [71] Ebert DH et al. 2013 Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341– 345. (doi:10.1038/nature12348) 23770587 PMC3922283 sourceExperimental — accuracy not yet measured

In the paper

“This suggests that the interruption of the MeCP2-NCoR1/SMRT complex interaction alone is capable of causing RTT-like phenotypes.”

What the sources say

• Supported

  The Discussion (page not provided) reports that Mecp2R306C mice lost the MeCP2–NCoR/SMRT interaction in the brain and exhibited an RTT-like phenotype. The paper presents loss of this interaction as a proposed explanation, consistent with the citing sentence’s 'suggests' qualifier. (LLM, conf=0.90)

  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

In the paper

“While Mecp2 mutant mice are an excellent model for RTT, elimination of MeCP2 affects the expression of a profound number of pathways in the CNS, making it difficult to pinpoint which ones play a key role in pathology [77,89,90].”

What the sources say

• Partly supported

  The gene-expression results (section labeled Abstract; page not provided) report thousands of altered genes in the hypothalamus of Mecp2-null and overexpressing mice, across distinct functional categories. The concluding passage says that restoring each affected gene may be challenging, but it does not say that identifying the pathways key to RTT pathology is difficult. The study examined the hypothalamus, not the CNS as a whole. (LLM, conf=0.84)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports hundreds of altered genes in the cerebellum and thousands in the hypothalamus, including genes involved in several neuronal processes. This supports widespread expression changes in brain regions of MeCP2-disorder mouse models, but the paper does not establish that a profound number of pathways are affected or say that this makes it difficult to identify which pathways drive RTT pathology. (LLM, conf=0.84)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘Pathway analysis in transcriptome and proteome implicate similar biological pathways’; page unavailable) reports diverse disrupted pathways in the cortex of Mecp2-deficient mice, supporting the claim that MeCP2 loss affects many pathways. The paper does not explicitly say that this makes it difficult to identify which pathways are key to RTT pathology, and its measurements are from cortex rather than the CNS as a whole. (LLM, conf=0.82)

  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 sourceExperimental — accuracy not yet measured

In the paper

“While both 129.Mecp2tm1.1Bird mice and B6.Mecp2tm1.1Jae mice show decreased sterol synthesis in the brain, elevated cholesterol and triglycerides in the serum and liver are observed only in 129.Mecp2tm1.1Bird mice [156].”

What the sources say

• Supported

  The Results section reports downregulation of brain cholesterol-biosynthesis genes in both Mecp2 alleles at P56 and describes downregulation of the synthesis pathway in 129.Mecp2tm1.1Bird mice. It also reports a direct assay confirming decreased brain sterol synthesis in B6.Mecp2tm1.1Jae mice. The quoted claim concerns brain synthesis, not the separate serum-and-liver clause in the citing sentence. (LLM, conf=0.88)

  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

In the paper

“This pivotal finding showed that developmental absence of MeCP2 does not irreversibly damage neurons, instilling hope that symptom reversal is possible in RTT patients.”

What the sources say

• Supported

  The passage labeled Abstract explicitly states that developmental absence of MeCP2 does not irreversibly damage neurons. The paper establishes this through reversal of neurological defects in a mouse model; it describes reversal in patients as a possibility, not a demonstrated outcome. (LLM, conf=0.95)

  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

In the paper

“Post-symptomatically, the overproduction of cholesterol decreases sterol synthesis in Mecp2 null brains due to regulatory feedback [156,171] (figure 4c).”

What the sources say

• Partly supported

  The Results section reports decreased sterol synthesis in symptomatic adult Mecp2 mutant brains and suggests that earlier cholesterol overproduction likely feeds back to decrease synthesis. The claim presents that proposed feedback mechanism as established rather than likely. (LLM, conf=0.84)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that brain sterol synthesis in Mecp2−/y mice falls beginning in the third postnatal week. It does not establish cholesterol overproduction or regulatory feedback as the cause: brain cholesterol concentration was unchanged, and the authors say the signal causing synthesis to fall is unknown. (LLM, conf=0.90)

  cites [171] Lopez AM, Chuang J-C, Posey KS, Turley SD 2017 Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis. Brain Res. 1654A, 77– 84. (doi:10.1016/j.brainres.2016.10.021) PMC5131633 27789278 sourceExperimental — accuracy not yet measured

In the paper

“Indeed, Kyle et al. [180] showed that Mecp2 mutant mice develop severe dyslipidaemia due to aberrant transcription of lipogenesis enzymes in the liver, because MeCP2 interacts with the NCoR1/SMRT-HDAC3 complex to repress lipogenic gene transcription.”

What the sources say

• Partly supported

  The Results (Figure 4) and Discussion show that hepatic MeCP2 associates with NCoR1, HDAC3, and TBLR1 and helps repress transcription at lipogenic loci. They do not show SMRT as a member of the liver complex tested here, so the SMRT-specific part of the claim is not established by this paper. (LLM, conf=0.85)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Notably, metabolic phenotypes differ in Mecp2 null mice across genetic backgrounds.”

What the sources say

• Supported

  The Results section (‘Mecp2 null males have abnormal cholesterol metabolism’) reports elevated liver triglycerides and serum lipids in the 129-background model but much smaller or no corresponding changes in the B6-background model. The Discussion likewise says that allele and genetic background likely affect the metabolic phenotype. (LLM, conf=0.88)

  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

In the paper

“Consistently, only a subset of RTT patients exhibit increased serum cholesterol and/or triglycerides [15,16,173].”

What the sources say

• Supported

  In “A Subset of Rett Patients Display Dyslipidemia,” the paper reports elevated cholesterol, triglycerides, and/or LDL in 52%, 44%, and 30% of the three pediatric age groups studied. These figures support the claim that elevated serum lipids occur in only a subset of RTT patients; the paper describes the retrospective data as preliminary. (LLM, conf=0.92)

  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
• Partly supported

  The Results and Discussion report significantly higher total and LDL cholesterol in RTT patients than in healthy controls, supporting the cholesterol portion of the claim. They report no variation in triglycerides and do not establish that the increases occur in only a subset of patients (page unavailable in our copy). (LLM, conf=0.85)

  cites [16] Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, Pallottini V 2014 Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE 9, e104834 (doi:10.1371/journal.pone.0104834) 25118178 PMC4130597 sourceExperimental — accuracy not yet measured
• Partly supported

  Section 3.1 and Table 1 report higher mean total cholesterol in RTT patients than in controls. Table 1 shows no increase in mean triglycerides, and the paper does not report how many individual patients had elevated cholesterol or triglycerides. It therefore supports the cholesterol finding but not the claim that only a subset of patients had either elevation. (LLM, conf=0.84)

  cites [173] Sticozzi C et al. 2013 Scavenger receptor B1 post-translational modifications in Rett syndrome. FEBS Lett. 587, 2199– 2204. (doi:10.1016/j.febslet.2013.05.042) 23711372 sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  The Discussion reports respiratory abnormalities in the Mecp2-null mouse brain, including reduced complex IV activity and loss of respiratory control. This directly supports the claim that an RTT animal model has mitochondrial respiratory-chain defects; the paper specifically studies a mouse model. (LLM, conf=0.93)

  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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Notably, MeCP2 directly represses Irak1 and downregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice [206].”

What the sources say

• Supported

  The Results section (‘Disrupted NF-κB contributes to pathogenesis of Mecp2-nulls’) reports that reducing Nfkb1 expression in Mecp2-null mice improved health, extended lifespan, and ameliorated abnormal dendritic complexity. This supports the attributed claim that reducing NF-κB signalling improves symptoms in these mice. (LLM, conf=0.94)

  cites [206] Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E, Macklis JD 2016 Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat. Commun. 7, 10520 (doi:10.1038/ncomms10520) 26821816 PMC4740176 source

In the paper

“Already, mutations in other components of the complex, TBLR1 and TBL1, have been associated with autism, intellectual disability, Pierpont syndrome, a disorder characterized by developmental delay and abnormal fat distribution in the distal limbs, and West syndrome, a disorder with RTT-like features [216–219].”

What the sources say

• Partly supported

  The Discussion reports that deletions spanning TBL1X and other genes have been associated with autism, including in a person with intellectual disability. It mentions TBL1XR1 as a related gene but does not link mutations in it to these conditions, and it does not address Pierpont or West syndrome. The reported regional deletions also do not establish that mutations specifically in TBL1X cause the conditions. (LLM, conf=0.85)

  cites [216] Chung R-H et al. 2011 An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males. Mol. Autism 2, 18 (doi:10.1186/2040-2392-2-18) 22050706 PMC3305893 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [217] Pons L, Cordier MP, Labalme A, Till M, Louvrier C, Schluth-Bolard C, Lesca G, Edery P, Sanlaville D 2015 A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am. J. Med. Genet. Part A 167, 164– 168. (doi:10.1002/ajmg.a.36759) 25425123 source
• Supported

  The Discussion identifies TBLR1 as another name for TBL1XR1 and reports TBL1XR1 mutations associated with autism, intellectual disability, and West syndrome. The Results identify a TBL1XR1 mutation as disease-causing in patients with Pierpont syndrome, which the Background describes as involving developmental delay and abnormal distal-limb fat distribution. The source directly supports the TBLR1 associations for which this citation is offered. (LLM, conf=0.91)

  cites [218] Heinen CA et al. 2016 A specific mutation in TBL1XR1 causes Pierpont syndrome. J. Med. Genet. 53, 330– 337. (doi:10.1136/jmedgenet-2015-103233) 26769062 PMC4853543 source
• ?Not checked — no full text of the sourcecites [219] Saitsu H et al. 2014 A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J. Hum. Genet. 59, 1– 3. (doi:10.1038/jhg.2014.71) 25102098 source

In the paper

“Additionally, abnormal lipid metabolism is directly linked to inflammation [204], which is a component of pathology in both typical and atypical cases of RTT [205].”

What the sources say

• Partly supported

  The Discussion reports a significant proinflammatory status in typical MECP2-RTT. It also reports cytokine dysregulation in CDKL5-RTT, but says this did not increase inflammatory marker levels and that its inflammatory status remains unclear. The claim therefore overstates the evidence for atypical CDKL5-RTT. (LLM, conf=0.88)

  cites [205] Leoncini S et al. 2015 Cytokine dysregulation in MECP2- and CDKL5-related Rett syndrome: relationships with aberrant redox homeostasis, inflammation, and ω-3 PUFAs. Oxid. Med. Cell. Longev. 2015, 421624 (doi:10.1155/2015/421624) 26236424 PMC4510261 sourceExperimental — accuracy not yet measured

In the paper

“Additionally, insulin-like growth factor (IGF-1) partially rescued locomotor activity, respiratory function and heart rate in Mecp2 mice [209,210].”

What the sources say

• Supported

  The Results report that rhIGF1 improved breathing and heart rates in Mecp2-null mice after six weeks of treatment (Fig. 1D–E). They also report significantly greater locomotor activity in treated than untreated Mecp2-null mice at P56 (Fig. 1F). (LLM, conf=0.93)

  cites [209] Castro J, Garcia RI, Kwok S, Banerjee A, Petravicz J, Woodson J, Mellios N, Tropea D, Sur M 2014 Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 9941– 9946. (doi:10.1073/pnas.1311685111) 24958891 PMC4103342 source
• ?Not checked — no full text of the sourcecites [210] Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M 2009 Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029– 2034. (doi:10.1073/pnas.0812394106) 19208815 PMC2644158 source

In the paper

“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].”

What the sources say

• Supported

  The Discussion reports altered brain oxidative-stress markers and oxidative-stress-driven brain damage in two Mecp2-mutant mouse models of Rett syndrome. This directly supports the claim that RTT animal models have oxidative changes in the brain. (LLM, conf=0.94)

  cites [203] De Felice C et al. 2014 Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol. Dis. 68, 66– 77. (doi:10.1016/j.nbd.2014.04.006) 24769161 PMC4076513 source

In the paper

“Additionally, abnormal lipid metabolism is directly linked to inflammation [204], which is a component of pathology in both typical and atypical cases of RTT [205].”

What the sources say

• Supported

  The Introduction describes LXRs as a signaling link between lipid metabolism and inflammation. Section 5b gives a more specific example: impaired macrophage cholesterol handling increases pro-inflammatory gene expression, directly linking cholesterol homeostasis to inflammation. The separate claim about RTT is attributed to [205], not this source. (LLM, conf=0.88)

  cites [204] Schulman IG 2017 Liver X receptors link lipid metabolism and inflammation. FEBS Lett. 591, 2978– 2991. (doi:10.1002/1873-3468.12702) 28555747 PMC5638683 source

In the paper

“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].”

What the sources say

• Supported

  The passage describing the astrocyte-specific knockout reports that removing MeCP2 produced features shared with MeCP2-null mice, including smaller body size, hindlimb clasping and irregular breathing. The effect was limited to a subset of RTT-like features: lifespan, locomotion and anxiety-related behavior remained normal. (LLM, conf=0.89)

  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
• Supported

  The Results section, “The loss of MeCP2 in oligodendrocyte lineage cells results in selective RTT-like behavioral deficits,” reports that mice lacking MeCP2 in these glial cells developed a mild RTT-like phenotype. The finding concerns oligodendrocyte-lineage cells specifically; it does not establish that deletion from every type of glial cell has the same effect. (LLM, conf=0.90)

  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

In the paper

“Notably, MeCP2 directly represses Irak1 and downregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice [206].”

What the sources say

• Partly supported

  In Results, under “CNS-specific mis-regulation of Irak1 in Mecp2-null mice” (page unavailable), MeCP2 binds upstream of Irak1, and reducing MeCP2 increases Irak1 expression. The authors say direct regulation is possible, but do not establish the unqualified claim that MeCP2 directly represses Irak1. (LLM, conf=0.86)

  cites [206] Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E, Macklis JD 2016 Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat. Commun. 7, 10520 (doi:10.1038/ncomms10520) 26821816 PMC4740176 sourceExperimental — accuracy not yet measured

In the paper

“Because Mecp2 mice preferentially metabolize fat rather than glucose as their primary energy source, it is likely that other energy-sensing systems are affected.”

What the sources say

• Supported

  The Results section, “Mecp2 deletion modifies whole body substrate metabolism,” reports that Mecp2 null mice had a markedly lower respiratory exchange ratio than wild-type littermates during both day and night, consistent with preferential lipid oxidation over carbohydrate metabolism. This supports the attributed claim about their energy source. (LLM, conf=0.93)

  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

In the paper

“Changes in brain carbohydrate metabolism [20] and neurometabolites associated with cell integrity and membrane turnover [21,22] have also been reported.”

What the sources say

• ?Not checked — no full text of the sourcecites [21] Hanefeld F, Christen HJ, Holzbach U, Kruse B, Frahm J, Hanicke W 1995 Cerebral proton magnetic resonance spectroscopy in Rett syndrome. Neuropediatrics 26, 126– 127. (doi:10.1055/s-2007-979742) 7566451 source
• ?Not checked — no full text of the sourcecites [22] Horska A, Naidu S, Herskovits EH, Wang PY, Kaufmann WE, Barker PB 2000 Quantitative 1H MR spectroscopic imaging in early Rett syndrome. Neurology 54, 715– 722. (doi:10.1212/WNL.54.3.715) 10680809 source

In the paper

“Additionally, energy-producing mitochondria have abnormal structure in patient cells [23–26].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [24] Eeg-Olofsson O, Al-Zuhair AG, Teebi AS, Daoud AS, Zaki M, Besisso MS, Al-Essa MM 1990 Rett syndrome: a mitochondrial disease?. J. Child Neurol. 5, 210– 214. (doi:10.1177/088307389000500311) 2168910 source
• ?Not checked — no full text of the sourcecites [25] Wakai S, Kameda K, Ishikawa Y, Miyamoto S, Nagaoka M, Okabe M, Minami R, Tachi N 1990 Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities. Pediatr. Neurol. 6, 339– 343. (doi:10.1016/0887-8994(90)90028-Y) 2242177 source
• ?Not checked — no full text of the sourcecites [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

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Knudsen GPS, Neilson TCS, Pedersen J, Kerr A, Schwartz M, Hulten M, Bailey MES, Ørstavik KH 2006 Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers. Eur. J. Hum. Genet. 14, 1189– 1194. (doi:10.1038/sj.ejhg.5201682) 16823396 source

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Rett A 1966 On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien. Med. Wochenschr. 1946, 723– 726. 5300597

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [17] Acampa M, Guideri F, Hayek J, Blardi P, De Lalla A, Zappella M, Auteri A 2008 Sympathetic overactivity and plasma leptin levels in Rett syndrome. Neurosci. Lett. 432, 69– 72. (doi:10.1016/j.neulet.2007.12.030) 18226448 source
• ?Not checked — no full text of the sourcecites [18] Blardi P, De Lalla A, D'Ambrogio T, Vonella G, Ceccatelli L, Auteri A, Hayek J 2009 Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin. Endocrinol. 70, 706– 709. (doi:10.1111/j.1365-2265.2008.03386.x) 18710461 source

In the paper

“However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems.”

In the paper

“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].”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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]).”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“Changes in brain carbohydrate metabolism [20] and neurometabolites associated with cell integrity and membrane turnover [21,22] have also been reported.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Matsuishi T, Urabe F, Percy AK, Komori H, Yamashita Y, Schultz RS, Ohtani Y, Kuriya N, Kato H 1994 Abnormal carbohydrate metabolism in cerebrospinal fluid in Rett syndrome. J. Child Neurol. 9, 26– 30. (doi:10.1177/088307389400900105) 8151077 source

In the paper

“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]).”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Matsuishi T, Urabe F, Percy AK, Komori H, Yamashita Y, Schultz RS, Ohtani Y, Kuriya N, Kato H 1994 Abnormal carbohydrate metabolism in cerebrospinal fluid in Rett syndrome. J. Child Neurol. 9, 26– 30. (doi:10.1177/088307389400900105) 8151077 source
• ?Not checked — no full text of the sourcecites [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

In the paper

“In neurons, MeCP2 serves as a bridge between the NCoR1/SMRT-HDAC3 complex and DNA to facilitate transcriptional repression, and mutations that affect MeCP2 binding to the complex cause RTT.”

In the paper

“These data suggest that at least a subset of RTT-like phenotypes in Mecp2 mutant mice are caused by the loss of HDAC3 in neurons.”

In the paper

“It is likely that at certain times and in specific cells, MeCP2 is required to anchor the NCoR1/SMRT-HDAC3 complex to DNA, regulating lipid production in some cells in the brain as in the liver.”

In the paper

“In neurons, MeCP2 serves as a bridge between the NCoR1/SMRT-HDAC3 complex and DNA to facilitate transcriptional repression, and mutations that affect MeCP2 binding to the complex cause RTT.”

In the paper

“Together, these data suggest that perturbed brain cholesterol synthesis is a common feature of Mecp2 null mice; however, it is likely that genetic background contributes to the Mecp2 null peripheral metabolic phenotype.”

In the paper

“Together, these data suggest that perturbed brain cholesterol synthesis is a common feature of Mecp2 null mice; however, it is likely that genetic background contributes to the Mecp2 null peripheral metabolic phenotype.”

In the paper

“These differential findings in mice suggested that peripheral lipid markers would not be elevated in all patients.”

In the paper

“Notably, background strain is unlikely to influence MeCP2's role in regulating liver lipid synthesis as both 129.Mecp2tm1.1Bird and B6.Mecp2tm1Bird/Y; Alb-Cre mice showed perturbed lipid metabolism.”

In the paper

“Importantly, these findings led to a phase 2 clinical trial for the pharmacological treatment of RTT with lovastatin (NCT02563860).”

In the paper

“Therefore, the transcriptional function of the NCoR1/SMRT complex could represent a shared mechanism for autism spectrum disorders and other neurological conditions.”

In the paper

“While MeCP2 has been largely studied in CNS development and maturation, some clinically significant aspects of RTT may arise independently of MECP2 deficiency in the nervous system, and should be considered when planning any treatment strategy.”