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Cited by 51Genetics and Neurodevelopmental DisordersCholesterol and Lipid MetabolismCancer, Lipids, and Metabolism

Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome

Open access
Segatto, Marco, Tonini, Claudia, Pfrieger, Frank W., Trezza, Viviana, Pallottini, Valentina·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20133317PMC PMC6651320
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Abstract

The mevalonate (MVA)/cholesterol pathway is crucial for central nervous system (CNS) development and function and consequently, any dysfunction of this fundamental metabolic pathway is likely to provoke pathologic changes in the brain. Mutations in genes directly involved in MVA/cholesterol metabolism cause a range of diseases, many of which present neurologic and psychiatric symptoms. This raises the question whether other diseases presenting similar symptoms are related albeit indirectly to the MVA/cholesterol pathway. Here, we summarized the current literature suggesting links between MVA/cholesterol dysregulation and specific diseases, namely autism spectrum disorder and Rett syndrome.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes evidence linking mevalonate/cholesterol pathway dysregulation to autism spectrum disorder (ASD) and Rett syndrome (RTT), alongside direct cholesterol disorders such as SLOS, NPC, and desmosterolosis. It concludes there are first hints of involvement in ASD and RTT, but no direct proof of causation, and calls for further studies.

Key findings

  • The brain contains 23% of body cholesterol while representing only 2% of body weight; CNS cholesterol must be synthesized in situ because lipoproteins cannot cross the blood-brain barrier, via the mevalonate pathway and its key enzyme HMGCR.
  • Direct MVA/cholesterol disorders include SLOS (DHCR7 mutations; severely affected patients can have cholesterol as low as 2% of normal), NPC (about 95% NPC1 and 5% NPC2 mutations), and desmosterolosis (DHCR24 mutations).
  • In ASD, a valproic acid rat model shows age-, region-, and sex-dependent cholesterol-related changes, including increased membrane-attached geranylgeranylated RhoA in cerebellum, reduced farnesylated Ras in nucleus accumbens, and reduced oligodendrocytes; a de novo LRP1 splice-site variant has been identified in ASD patients, and ASD is more frequent in boys than girls at a ratio of 3:1.
  • In RTT, 95% of cases are caused by MECP2 mutations; patients show increased plasma total cholesterol, LDL-cholesterol, and HDL-cholesterol, reduced SR-B1 in fibroblasts, and dramatically reduced HMGCR activity with increased HMGCR protein; lovastatin improved systemic lipid profile, motor behaviors, and lifespan in Mecp2-null mice, but another study found no effect in a different genetic background.

Methods

  • Narrative literature review; no primary experimental study or systematic review/meta-analysis is described.
  • Synthesizes published human, patient-derived, and rodent-model evidence, including plasma and primary fibroblast studies in RTT, VPA-exposed rat models of ASD, and Mecp2-null mouse models.
  • Main analysis is qualitative integration of findings linking MVA/cholesterol metabolism to ASD and RTT, with comparison to diseases directly caused by cholesterol pathway mutations.

Limitations

  • Stated: there is no direct proof that ASD and RTT are caused by defects in the MVA/cholesterol pathway; further studies are needed to address causal links, underlying mechanisms, specific brain cell types, and whether MVA/cholesterol metabolism is a pharmacological target.
  • Stated: reliability of experimental models needs clarification; unknown modifiers may affect lovastatin efficacy; atypical RTT patients with mutations other than MECP2 remain to be assessed.
  • Evident: as a narrative review, no systematic search or selection criteria are reported; many disease links are associative, and the paper itself notes that blood cholesterol levels are independent from brain cholesterol and that correlations cannot establish causal relations.

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

Integrity signals

Registry

Crossref · 10.3390/ijms20133317

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

37 of 69 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A second study performed on Mecp2-deficient mice with a different genetic background showed no effect of lovastatin.

    “whereas a second study performed on Mecp2-deficient mice with a different genetic background show no effect of lovastatin [81].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [81] Villani, 2016, Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice, Elife source
  • Premisecitation

    Alterations were also observed in the amount of serum cholesterol derived from Mecp2-null mice, which was significantly increased.

    “Alterations were also observed in the amount of serum cholesterol derived from Mecp2-null mice, which was significantly increased [77].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [77] Buchovecky, 2013, A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome, Nat. Genet. source
  • Findingcitation

    Our studies support an involvement of cholesterol metabolism in RTT patients harboring mutations in the Mecp2 gene.

    “Our studies support an involvement of cholesterol metabolism in RTT patients harboring mutations in Mecp2 gene [14,75].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] Fracassi, 2019, Statins and the Brain: More than Lipid Lowering Agents?, Curr. Neuropharmacol. source
    • cites [75] Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., and Pallottini, V. (2014). Cholesterol metabolism is altered in Rett syndrome: A study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE, 9. source
  • Premisecitation

    RTT is deeply associated to important metabolic alterations.

    “It is becoming increasingly clear that RTT is deeply associated to important metabolic alterations [67].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [67] Kyle, S.M., Vashi, N., and Justice, M.J. (2018). Rett syndrome: A neurological disorder with metabolic components. Open Biol., 8. source
  • Findingown data

    We highlighted a concurrent increase in the protein amount of HMGCR in RTT fibroblasts.

    “Together with the reduction in HMGCR activity, we highlighted a concurrent increase in the protein amount of HMGCR in RTT fibroblasts.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., and Pallottini, V. (2014). Cholesterol metabolism is altered in Rett syndrome: A study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE, 9. source
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationcitation

    Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations in SLOS.

    “Low cholesterol levels may impair sonic hedgehog signaling and cause the striking developmental malformations. Activity of this signaling factor and its distribution are regulated by posttranslational attachment of cholesterol to its amino terminus [26,27,28].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [26] Porter, 1996, Hedgehog patterning activity: Role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain, Cell source

      The Abstract and Discussion report that a lipophilic modification influences Hedgehog signaling activity and distribution. But the paper does not identify the modifying group as cholesterol; its discussion of “The Nature of the Modification” places the linkage at the carboxyl terminus of the amino-terminal signaling domain, not at its amino terminus. The citation is attached to the modification sentence, not the preceding sentence about low cholesterol and malformations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [27] Cooper, 1998, Teratogen-mediated inhibition of target tissue response to Shh signaling, Science source
    • cites [28] Koide, 2006, Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase, Development source

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

    Premisecitation

    Cholesterol is enriched in dynamic structures called lipid rafts that play important roles in signal transduction across membranes.

    “Cholesterol is not homogeneously dispersed within membranes: it is more abundant in the cytosolic part of the plasma membrane [4] and it is enriched in dynamic structures called “lipid rafts” that play important roles in signal transduction across membranes [5].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Wang, 2014, Lipid rafts: A signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders, Front. Behav. Neurosci. source

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

    Premisecitation

    The brain contains 23% of the cholesterol in the human body although it represents only 2% of total body weight.

    “The brain contains 23% of the cholesterol in the human body although it represents only the 2% of the total body weight [1] indicating the importance of this molecule for the central nervous system (CNS).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [1] Dietschy, 2004, Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal, J. Lipid Res. source

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

    Premisecitation

    The synthesis of cholesterol in the CNS is assured by the mevalonate pathway, which starts from acetate and comprises about 30 enzymatic reactions.

    “The synthesis of this lipid is assured by the so-called mevalonate (MVA) pathway [14] that starts from acetate and comprises a series of ~30 enzymatic reactions.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Fracassi, 2019, Statins and the Brain: More than Lipid Lowering Agents?, Curr. Neuropharmacol. source

      The Introduction identifies the mevalonate pathway as a major source of cholesterol, and the Cholesterol section says de novo synthesis supplies practically all cholesterol in the CNS (page numbers unavailable). Our copy does not state that the pathway starts from acetate or comprises approximately 30 enzymatic reactions. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Diet-derived cholesterol cannot cross the BBB and cannot compensate the low cholesterol level in the brain of SLOS patients with neurologic symptoms.

    “Nevertheless, diet-derived cholesterol cannot cross the BBB and cannot compensate the low cholesterol level in the brain [3,24].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Segatto, 2014, Cholesterol homeostasis failure in the brain: Implications for synaptic dysfunction and cognitive decline, Curr. Med. Chem. source
    • cites [24] Martin, 2014, Cholesterol in brain disease: Sometimes determinant and frequently implicated, EMBO. Rep. source

  • May combine two claims.

    Premisecitation

    The most severe DHCR7 mutations cause fetal or newborn death, while less severe variants cause developmental defects in specific organs such as facial and cranial malformations, hypospadia or complete gonadal absence.

    “The most severe mutations of this gene cause fetal or newborn death, while less severe variants cause developmental defects in specific organs such as facial and cranial malformations, hypospadia or complete gonadal absence [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Martin, 2014, Cholesterol in brain disease: Sometimes determinant and frequently implicated, EMBO. Rep. source

  • The quote only partly states this claim.

    Findingown data

    We reported a dramatic reduction in the activity of HMGCR in RTT fibroblasts.

    “Importantly, we reported a dramatic reduction in the activity of HMGCR.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [75] Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., and Pallottini, V. (2014). Cholesterol metabolism is altered in Rett syndrome: A study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE, 9. source

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

    Premisecitation

    MeCP2 plays a key role in gene silencing through methylation-dependent remodeling of chromatin structure, and suppresses gene transcription through association with several co-repressors.

    “This protein plays a key role in gene silencing through methylation-dependent remodeling of chromatin structure, and suppresses gene transcription through the association with several co-repressors [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Fracassi, 2019, Statins and the Brain: More than Lipid Lowering Agents?, Curr. Neuropharmacol. source

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

    Premisereasoning

    ASD is by now considered as a multifactorial disease.

    “For this reason, ASD is by now considered as a multifactorial disease [95,96,97].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [95] Jeste, 2014, Disentangling the heterogeneity of autism spectrum disorder through genetic findings, Nat. Rev. Neurol. source
    • cites [96] Chaste, 2012, Autism risk factors: Genes, environment, and gene-environment interactions, Dialogues Clin. Neurosci. source
    • cites [97] Lord, 2006, The developmental neurobiology of autism spectrum disorder, J. Neurosci. source

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

    Premisecitation

    Several diseases including Alzheimer, Huntington, and Parkinson diseases are thought to involve changes in cholesterol metabolism although a direct link cannot be established.

    “Several diseases including Alzheimer, Huntington, and Parkinson diseases are thought to involve changes in cholesterol metabolism although a direct link cannot be established [14] (Table 1).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Fracassi, 2019, Statins and the Brain: More than Lipid Lowering Agents?, Curr. Neuropharmacol. source

      The Alzheimer’s Disease and Huntington’s Disease sections link both conditions to altered cholesterol metabolism. The Parkinson’s Disease section reports an association between total cholesterol level and Parkinson’s risk, but does not establish altered cholesterol metabolism in Parkinson’s disease. Its uncertainty concerns that association and statin effects, rather than a direct link across all three diseases; page numbers are unavailable in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Lovastatin significantly improved systemic lipid profile, ameliorated motor behaviors and increased lifespan of Mecp2-null mice.

    “Lovastatin significantly improved systemic lipid profile, ameliorated motor behaviors and increased lifespan of Mecp2-null mice [77], whereas a second study performed on Mecp2-deficient mice with a different genetic background show no effect of lovastatin [81].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Buchovecky, 2013, A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome, Nat. Genet. source

      The Results section (page unavailable) reports that lovastatin ameliorated motor symptoms in 129.Mecp2-null male mice, measured by rotarod and open-field activity. It attributes lowered cholesterol and increased lifespan specifically to fluvastatin; the copy does not establish those outcomes for lovastatin. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The first report linking RTT to cholesterol metabolism demonstrated enhanced levels of plasma total cholesterol, LDL-cholesterol and HDL-cholesterol in RTT patients, whereas no significant change was observed in the amount of total triglycerydes.

    “The first report linking RTT to cholesterol metabolism demonstrated enhanced levels of plasma total cholesterol, LDL (low density lipoprotein)-cholesterol and HDL (High density lipoprotein)-cholesterol in RTT patients, whereas no significant change was observed in the amount of total triglycerydes [102], suggesting that dysbalance in plasma lipid profile is restricted to cholesterol metabolism.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [102] Sticozzi, 2013, Scavenger receptor B1 post-translational modifications in Rett syndrome, FEBS. Lett. source

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

    Premisecitation

    Cholesterol has been implied in the production and clearance of beta amyloid.

    “Cholesterol has been implied in the production and clearance of beta amyloid [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Martin, 2014, Cholesterol in brain disease: Sometimes determinant and frequently implicated, EMBO. Rep. source

  • May combine two claims.

    Findingcitation

    We observed a significant increase of total cholesterol and LDL-cholesterol plasma levels, and a decrease of SR-B1 protein expression in primary fibroblasts derived from RTT patients.

    “In agreement with other preclinical and clinical data [77,102], we observed a significant increase of total cholesterol and LDL-cholesterol plasma levels, and a decrease of SR-B1 protein expression in primary fibroblasts derived from RTT patients [75].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [75] Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., and Pallottini, V. (2014). Cholesterol metabolism is altered in Rett syndrome: A study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE, 9. source

  • May combine two claims.

    Premisecitation

    An independent group showed significant dysregulated expression of genes involved in cholesterol biosynthesis, such as Hmgcr and Squalene Epoxidase (Sqle), in both brains and livers of Mecp2-null mice and a concurrent reduction of cholesterol precursors and a decrease of cholesterol biosynthesis in the brain.

    “Few months after, an independent group showed significant dysregulated expression of genes involved in cholesterol biosynthesis, such as Hmgcr and Squalene Epoxidase (Sqle), in both brains and livers of Mecp2-null mice and a concurrent reduction of cholesterol precursors and a decrease of cholesterol biosynthesis in the brain [77,78,79].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [77] Buchovecky, 2013, A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome, Nat. Genet. source
    • cites [78] Lopez, 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. 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
    • cites [79] Lutjohann, 2018, Identification of Correlative Shifts in Indices of Brain Cholesterol Metabolism in the C57BL6/Mecp2(tm1.1Bird) Mouse, a Model for Rett Syndrome, Lipids source

  • May combine two claims.

    Premisecitation

    Defects in LRP1 result in degeneration of dendritic spines and synapses and in neuroinflammation.

    “Defects in this protein result in degeneration of dendritic spines and synapses and in neuroinflammation [100].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Liu, 2010, Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration, J. Neurosci. source

  • May combine two claims.

    Findingown data

    Our research group demonstrated that cholesterol biosynthesis and uptake are differently modulated in different brain regions of adult male rats, with HMGCR activity very low in the brain stem and high in hippocampus, brain cortex and cerebellum.

    “In particular, our research group demonstrated that cholesterol biosynthesis and uptake are differently modulated in different brain regions of adult male rats. The HMGCR activity is very low in the brain stem, and high in hippocampus, brain cortex and cerebellum.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Segatto, 2012, Regulation of cholesterol biosynthetic pathway in different regions of the rat central nervous system, Acta. Physiol. (Oxf) source
    • cites [23] Segatto, 2011, Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor, J. Cell Physiol. source

  • May combine two claims.

    Premisenone given

    Cholesterol is a main component of synaptic vesicles, and their formation, shape, and release are critically dependent on this lipid.

    “Specifically, cholesterol is a main component of synaptic vesicles: their formation, shape, and release are critically dependent on this lipid.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Some SLOS patients show intellectual disability, perturbed sleep, delayed acquisition of motor and language skills as well as impaired social interactions.

    “Some SLOS patients show intellectual disability, perturbed sleep, delayed acquisition of motor and language skills as well as impaired social interactions.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    NPC patients present with highly variable age of onset, neurovisceral symptoms, and life-span ranging from a few years to decades of life.

    “NPC patients present with highly variable age of onset, neurovisceral symptoms, and life-span ranging from a few years to decades of life.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Approximately 95% and 5% of NPC cases are caused by mutations in the NPC1 and NPC2 genes, respectively.

    “Approximately 95% and 5% of cases are caused by mutations in the ubiquitously expressed Niemann-Pick type C 1 (NPC1) and NPC2 gene, which encode for a large membrane glycoprotein in late endosomes, and for a small soluble lysosomal protein, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    An imbalance in cholesterol homeostasis both at the presynaptic and postsynaptic side is likely to impact neurotransmission and induce the loss of synapses and dendritic spines.

    “Thus, an imbalance in cholesterol homeostasis both at the presynaptic and postsynaptic side is likely to impact neurotransmission, and induce the loss of synapses and dendritic spines [11,12].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Sooksawate, 2001, Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones, Neuropharmacology source
    • cites [12] Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science source

  • May combine two claims.

    Premisecitation

    Neurons produce cholesterol during prenatal life and depend on cholesterol synthesis by astrocytes after birth.

    “Several studies suggest that neurons produce cholesterol during prenatal life and depend on cholesterol synthesis by astrocytes after birth [12,13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science source
    • cites [13] Pfrieger, 2011, Cholesterol metabolism in neurons and astrocytes, Prog. Lipid. Res. source

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

    Premisecitation

    MVA is the precursor of compounds other than cholesterol that are involved in transcription, protein N-glycosylation, protein prenylation, and mitochondrial electron transport.

    “Importantly, MVA is the precursor of compounds other than cholesterol that are involved in diverse cellular processes such as transcription (isopentenyl tRNAs), protein N-glycosylation (dolichol phosphate), protein prenylation (farnesylation and geranylgeranylation), and mitochondrial electron transport (ubiquinone) (Figure 1) [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Ikonen, 2006, Mechanisms for cellular cholesterol transport: Defects and human disease, Physiol. Rev. source

  • May combine two claims.

    Premisecitation

    Cholesterol is a key constituent of myelin sheaths and neuronal membranes.

    “Cholesterol is a key constituent of myelin sheaths and neuronal membranes [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Pfrieger, 2003, Outsourcing in the brain: Do neurons depend on cholesterol delivery by astrocytes?, Bioessays source

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

    Premisecitation

    Niemann-Pick type C disease (NPC) is characterized by intracellular accumulation of unesterified cholesterol and glycolipids in the endosomal/lysosomal system.

    “The pathology is characterized by intracellular accumulation of unesterified cholesterol and glycolipids in the endosomal/lysosomal system [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Vanier, 2003, Niemann-Pick disease type C, Clin. Genet. source

  • May combine two claims.

    Premisecitation

    Accumulation of 7-dehydrocholesterol in fibroblasts impairs intracellular cholesterol transport and increases the degradation rate of HMGCR, contributing to reduced sterol synthesis in SLOS patients.

    “It has been demonstrated that the accumulation of 7-DHC in fibroblasts impairs intracellular cholesterol transport and increases the degradation rate of HMGCR, contributing to a reduced sterol synthesis in SLOS patients [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Wassif, 2003, 27-Hydroxylation of 7- and 8-dehydrocholesterol in Smith-Lemli-Opitz syndrome: A novel metabolic pathway, Steroids source

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

    Premisecitation

    Autism spectrum disorder (ASD) refers to a range of developmental psychiatric disorders characterized by deficits in social communication and interactions, restricted interests and repetitive behaviors that appear during the first two years of life.

    “ASD refers to a range of developmental psychiatric disorders characterized by deficits in social communication and interactions, restricted interests and repetitive behaviors that appear during the first two years of life [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Lai, 2014, Autism, Lancet source

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

    Premisecitation

    A specific variant of the gene encoding apolipoprotein E is one of the best established risk factors for late onset/sporadic Alzheimer's disease.

    “A specific variant of the gene encoding for apolipoprotein E, which transports cholesterol in the brain, is one of the best established risk factors for late onset/sporadic AD [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Wang, 2005, Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology, Neurobiol. Dis. source

  • May combine two claims.

    Premisecitation

    The VPA rat model includes changes in the activation state of HMGCR and in the levels of several receptors mediating cholesterol uptake and release.

    “This includes changes in the activation state of HMGCR and in the levels of several receptors mediating cholesterol uptake and release.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Rett syndrome (RTT) is an X-linked neurological disorder affecting only females with a prevalence of 1 out of 10,000 live births.

    “RTT is a X-linked neurological disorder affecting only female with a prevalence of 1 out of 10,000 live births [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Patankar, 2014, Cholesterol metabolism is a potential therapeutic target for Rett syndrome, Clin. Genet. source

  • May combine two claims.

    Premisecitation

    Individuals affected by RTT display a decrease in brain volume and a concomitant reduction in head circumference.

    “Individuals affected by RTT display a decrease in brain volume and a concomitant reduction in head circumference [68,69], which are strongly associated to a smaller size of neurons and to an enhanced compaction of cells, particularly at the level of layers III and V of the cerebral cortex, substantia nigra, thalamus, cerebellum, basal ganglia, hippocampus and amygdala [70].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Jellinger, 1986, Neuropathology of Rett syndrome, Am. J. Med. Genet. Suppl. source
    • cites [69] Jellinger, 1988, Neuropathology of Rett syndrome, Acta. Neuropathol. source

  • May combine two claims.

    Premisenone given

    Patients with desmosterolosis present microcephalia, hydrocephalia, ventricular enlargement, defects in the corpus callosum, and thinning of white matter and seizures.

    “Patients with desmosterolosis present microcephalia, hydrocephalia, ventricular enlargement, defects in the corpus callosum, and thinning of white matter and seizures.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Blood levels of cholesterol are completely independent from the brain and correlations between cholesterolemia and behavior cannot establish causal relations.

    “However, the studies correlating cholesterolemia and behavior have to be carefully considered since blood levels of cholesterol are completely independent from the brain and correlations cannot establish causal relations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    It has been demonstrated in vitro that mutant huntingtin represses genes involved in cholesterol metabolism possibly due to a lower transcriptional activity of SREBP2.

    “It has been demonstrated in vitro that mutant HTT represses genes involved in cholesterol metabolism [50] possibly due to a lower transcriptional activity of the Sterol Regulatory Element Binding Protein 2 (SREBP2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Sipione, 2002, Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses, Hum. Mol. Genet. source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mutations in genes directly involved in MVA/cholesterol metabolism cause a range of diseases, many of which present neurologic and psychiatric symptoms (e.g., SLOS, NPC, desmosterolosis).

    “Mutations in genes directly involved in MVA/cholesterol metabolism cause a range of diseases, many of which present neurologic and psychiatric symptoms (e.g. SLOS, NPC, desmosterolosis).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several studies suggest possible correlations between mood disorders and altered cholesterol levels, both in brain and blood.

    “Several studies suggest possible correlations between mood disorders and altered cholesterol levels, both in brain and blood [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Golomb, 2008, Statin adverse effects: A review of the literature and evidence for a mitochondrial mechanism, Am. J. Cardiovasc. Drugs source

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

    Premisenone given

    In 95% of the cases, RTT is caused by mutations in the gene encoding methyl CpG binding protein 2 (MECP2).

    “In 95% of the cases, RTT is caused by mutations in gene encoding for methyl CpG binding protein 2 (MECP2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adolescent VPA-exposed rats showed a strong increase of membrane-attached geranylgeranylated RhoA in the cerebellum, a reduced level of the farnesylated Ras in the Nucleus Accumbens and a reduction of oligodendrocytes.

    “Adolescent VPA-exposed rats showed a strong increase of membrane-attached geranylgeranylated RhoA in the cerebellum, a reduced level of the farnesylated Ras in the Nucleus Accumbens and a reduction of oligodendrocytes were observed [55].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Cartocci, 2018, Altered Brain Cholesterol/Isoprenoid Metabolism in a Rat Model of Autism Spectrum Disorders, Neuroscience source
39 of 39

  • The paper relies on this without support.

    Alterations in MVA/cholesterol metabolism observed in ASD and RTT models or patients contribute causally to the pathogenesis of these disorders rather than being secondary consequences.

    “These changes suggest that low intracellular cholesterol content, as a consequence of HMGCR activity suppression in RTT fibroblasts, induces the classic feedback mechanism with activation of SREBP2 and the increase of its transcriptional targets such as LDLR (LDL receptor) and HMGCR [23,55,103,104,105,106,107].”

  • The paper relies on this without support.

    Findings from VPA-exposed rats and Mecp2-null mice are relevant to human ASD and RTT.

    “A recent study reveals age- and region-dependent alterations of proteins involved in cholesterol metabolism in the brains of a well-established rat model [54] based on prenatal exposure to valproic acid (VPA) [55].”
    “Our studies support an involvement of cholesterol metabolism in RTT patients harboring mutations in Mecp2 gene [14,75].”
2 of 2

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?

Cites

Flagged first, then by citations

3 of the 114 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Elias, 1997, Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS), Am. J. Med. Genet., 68, 305, 10.1002/(SICI)1096-8628(19970131)68:3<305::AID-AJMG11>3.0.CO;2-X · DOI
  2. Nwokoro, 1997, Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome, Am. J. Med. Genet., 68, 315, 10.1002/(SICI)1096-8628(19970131)68:3<315::AID-AJMG13>3.0.CO;2-W · DOI

Cited by

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Related

Authors
Segatto, M., Tonini, C., Pfrieger, F. W., Trezza, V., & Pallottini, V.
Affiliations
  • University of Molise (IT)
  • Roma Tre University (IT)
  • Centre National de la Recherche Scientifique (FR)
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-07-05
Volume
20
Issue
13
Pages
3317
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20133317
PMC
PMC6651320
OpenAlex
W2953630508
Cited by
51
References
114
Citations by year
2026: 7 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 1
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
  • Iris (Roma Tre University) (submittedVersion)
Funders
Ministero dell’Istruzione, dell’Università e della Ricerca (2015SHM58M_004, Departments of Excellence - 2017 - legge 232/2016 - art.1, commi 314–337 awarded to Dept. of Science - University Roma Tre - Rome - Italy for 2018–2022)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
cholesterol homeostasis, autism spectrum disorder, Rett syndrome, brain metabolism, brain development, genetic mutations
MeSH terms
Autism Spectrum Disorder, Animals, Brain, Cholesterol, Homeostasis, Humans, Mevalonic Acid, Rett Syndrome

About these checks

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.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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