Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits

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

Dysregulated miRNA has been implicated in ASD.

“Dysregulated miRNA has been implicated in ASD [6–8].”

• cites [6] Hicks SD, Middleton FA. A comparative review of microRNA expression patterns in autism spectrum disorder. Front Psychiatry. 2016;7:176. sourceSupported
• cites [7] Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, et al. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008;9:153–61. sourceNot checked — no full text of the source
• cites [8] Talebizadeh Z, Butler MG, Theodoro MF. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res. 2008;1:240–50. sourceSupported

Classified as probably not a substantial claim.

Cholesterol and desmosterol play essential roles during embryogenesis, myelination, and brain development.

“cholesterol and desmosterol play essential roles during embryogenesis, myelination, and brain development [2–4].”

• cites [2] Howard E, Granoff DM, Bujnovszky P. DNA, RNA, and cholesterol increases in cerebrum and cerebellum during development of human fetus. Brain Res. 1969;14:697–706. sourceNot checked — no full text of the source
• cites [3] Hamilton JJ, Synnes A, Innis SM. Plasma cholesterol and lathosterol levels in term infants in the early neonatal period. Pediatr Res. 1992;31:396–400. sourceNot checked — no full text of the source
• cites [4] Mutka AL, Lusa S, Linder MD, Jokitalo E, Kopra O, Jauhiainen M, et al. Secretion of sterols and the NPC2 protein from primary astrocytes. J Biol Chem. 2004;279:48654–62. sourcePartly supported

  The Abstract says most brain sterol is acquired during early-development myelination, and the Discussion reports desmosterol in developing brain and embryonic astrocytes. These passages connect the sterols to development and myelination, but do not establish that both play essential roles in embryogenesis, myelination, and brain development. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Cholesterol does not cross from the periphery into the central nervous system, and small HDL particles possibly traverse by endocytosis to a small extent.

“Cholesterol does not cross from the periphery into the central nervous system (CNS) and small HDL particles possibly traverse by endocytosis to a small extent [15].”

• cites [15] Fung KY, Wang C, Nyegaard S, Heit B, Fairn GD, Lee WL, et al. SR-BI mediated transcytosis of HDL in brain microvascular endothelial cells is independent of Caveolin, Clathrin, and PDZK1. Front Physiol. 2017;8:841. sourcePartly supported

  The Introduction (page unavailable) says HDL can cross the blood–brain barrier by transcytosis, which involves endothelial internalization, and the Conclusion reports HDL moving from the apical to the basolateral surface in a cell model. The paper does not specify that the particles are small or that only a small amount crosses. It also does not establish the categorical claim that peripheral cholesterol cannot enter the CNS. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

HDL transports proteins, hormones, carotenoids, vitamins, bioactive lipids, and 90% of extracellular miRNA, and a reduction in HDL levels leads to reduced miRNA and changes in gene expression.

“HDL also transports proteins, hormones, carotenoids, vitamins, bioactive lipids, and 90% of extracellular micro-ribonucleic acids (miRNA), and a reduction in HDL levels leads to reduced miRNA and changes in gene expression [5].”

• cites [5] Vickers KC, Palmisano BT, Bassem S, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423. sourcePartly supported

  The Discussion (page not provided) states that HDL transports miRNAs and that HDL-mediated delivery can alter gene expression in recipient cells. It also describes HDL as carrying lipids and proteins, but our copy does not substantiate the full list of other cargo, the claim that HDL carries 90% of extracellular miRNA, or the proposed effect of reduced HDL levels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders.

“Altered cholesterol, HDL and LDL metabolism, gene variants of APOA1, APOB, and APOE4, and decreased ApoA1 levels have been implicated in other neurologic disorders [21–35].”

• cites [21] Huang X, Abbott RD, Petrovitch H, Mailman RB, Ross GW. Low LDL cholesterol and increased risk of Parkinson’s disease: prospective results from Honolulu-Asia Aging Study. Mov Disord. 2008;23:1013–8. sourceNot checked — no full text of the source
• cites [22] Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, et al. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci. 2005;25:9932–39. sourcePartly supported

  The Introduction (page unavailable) links defects in cholesterol homeostasis to Niemann–Pick type C and Alzheimer’s disease, and the Discussion reports impaired cholesterol biosynthesis in Huntington’s disease. The paper does not establish the claimed links involving HDL or LDL metabolism, APOA1, APOB or APOE4 variants, or decreased ApoA1 levels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [23] Karasinska JM, Hayden MR. Cholesterol metabolism in Huntington’s disease. Nat Rev Neurol. 2011;7:561–72. sourceNot checked — no full text of the source
• cites [24] Benarroch EE. Brain cholesterol metabolism and neurologic disease. Neurology. 2008;71:1368–73. sourceNot checked — no full text of the source
• cites [25] Zhang Q, Xu F, Wang L, Zhang WD, Sun CQ, Deng HW, et al. Detecting potential causal relationship between multiple risk factors and Alzheimer’s disease using multivariable Mendelian randomization. Aging (Albany NY). 2020;12:21747–57. sourcePartly supported

  The Results (mvMR estimates results; page unavailable) associate HDL, LDL, and total cholesterol levels with Alzheimer’s disease risk, supporting the lipid-related part of the claim for that disorder. The paper does not establish altered lipid metabolism across other neurologic disorders, nor does it report associations involving APOA1, APOB, or APOE4 variants or decreased ApoA1 levels. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [26] Zeng P, Zhou X. Causal effects of blood lipids on amyotrophic lateral sclerosis: a Mendelian randomization study. Hum Mol Genet. 2019;28:688–97. sourcePartly supported

  The Introduction (page unavailable) describes abnormal HDL, LDL, and total-cholesterol levels in people with ALS, and the Results (page unavailable) associate higher LDL with increased ALS risk. The paper does not establish an HDL effect or implicate APOA1, APOB, APOE4 variants, or decreased ApoA1 levels; it addresses ALS rather than neurologic disorders generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [27] Meyers L, Groover CJ, Douglas J, Lee S, Brand D, Levin MC, et al. A role for Apolipoprotein A-I in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2014;277:176–85. sourceNot checked — no full text of the source
• cites [28] Kawano M, Kawakami M, Otsuka M, Yashima M, Yaginuma H, Ueki T, Marked A, et al. Marked decrease of plasma apolipoprotein AI and AII in Japanese patients with late-onset non-familial Alzheimer’s disease. Clin Chim Acta. 1995;239:209–11. sourceNot checked — no full text of the source
• cites [29] Button EB, Robert J, Caffrey TM, Fan J, Zhao W, Wellington CL, et al. HDL from an Alzheimer’s disease perspective. Curr Opin Lipidol. 2019;30:224–34. sourcePartly supported

  The Epidemiological Evidence section (page unavailable) links lower HDL-C and apoA-I levels with Alzheimer’s disease, and Figure 1 identifies APOE4 as a genetic risk factor. The cited paper does not establish the claimed involvement of APOA1 or APOB gene variants, or altered LDL metabolism, in neurologic disorders. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [30] Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36:411–23. sourceNot checked — no full text of the source

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

The adrenal glands obtain cholesterol from HDL and LDL to synthesize steroid hormones and neuroactive steroids.

“The adrenal glands obtain cholesterol from HDL and LDL to synthesize steroid hormones and neuroactive steroids [9, 10].”

• cites [9] Bochem AE, Holleboom AG, Romijn JA, Hoekstra M, Dallinga-Thie GM, Motazacker MM, et al. High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C. J Lipid Res. 2013;54:1698–1704. sourcePartly supported

  The paper’s introductory passages say adrenal steroid-hormone synthesis requires cholesterol and support HDL as a cholesterol donor. They also say LDL probably does not play a major role in delivering cholesterol for steroid-hormone production in humans. The cited passages do not address neuroactive-steroid synthesis, so the full claim is not supported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [10] Borkowski AJ, Levin S, Delcroix C, Mahler A, Verhas V. Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation. J Clin Investig. 1967;46:797–811. sourcePartly supported

  The Introduction and Discussion report that adrenal glands use plasma cholesterol to produce hydrocortisone, a steroid hormone. But the Discussion explicitly says the study does not determine how adrenal tissue distinguishes among cholesterol carried by different lipoproteins; it does not establish uptake from both HDL and LDL. The passages also do not address neuroactive steroids (page numbers unavailable in our copy). (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

Cholesterol, HDL-like particles, and apolipoprotein E are synthesized in situ by glial cells.

“Therefore, cholesterol, HDL-like particles, and apolipoprotein E (ApoE) are synthesized in situ by glial cells [16–18].”

• cites [16] Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Investig. 1985;76:1501–13. sourcePartly supported

  The Discussion (page not available) identifies apoE as a secretory product of astrocytes and reports that cultured astrocytes produce it. The paper does not establish that glial cells synthesize cholesterol or HDL-like particles in situ; it discusses cholesterol transport and HDL particles, not their synthesis by glia. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [17] Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12:105–12. sourceNot checked — no full text of the source
• cites [18] Vitali C, Wellington CL, Calabresi L. HDL and cholesterol handling in the brain. Cardiovasc Res. 2014;103:405–13. sourceNot checked — no full text of the source

May combine two claims.

Decreased neuroactive steroid levels and sterol-related abnormal levels of cortisol, testosterone, estrogen, progesterone, and vitamin D have been reported in ASD.

“Decreased neuroactive steroid levels [11] and sterol-related abnormal levels of cortisol, testosterone, estrogen, progesterone, and vitamin D have been reported in ASD [12–14].”

• cites [11] Strous RD, Golubchik P, Maayan R, Mozes T, Tuati-Werner D, Weizman A, et al. Lowered DHEA-S plasma levels in adult individuals with autistic disorder. Eur Neuropsychopharmacol. 2005;15:305–9. sourceNot checked — no full text of the source
• cites [12] Aneja A, Tierney E. Autism: the role of cholesterol in treatment. Int Rev Psychiatry. 2008;20:165–70. sourceNot checked — no full text of the source
• cites [13] Lee RW, Tierney E. Hypothesis: the role of sterols in autism spectrum disorder. Autism Res Treat. 2011:653570. sourceCould not verify

  Section 4, “Neurosteroids and ASD” (page unavailable), discusses possible altered neurosteroid synthesis in Smith-Lemli-Opitz syndrome, not reported levels of the five named substances in ASD. A search for cortisol, testosterone, estrogen, progesterone, and vitamin D found no passage in our copy reporting those abnormalities in ASD. The separate claim about decreased neuroactive steroids carries a different citation [11]. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [14] Gillberg C, Fernell E, Kocovska E, Minnis H, Bourgeron T, Thompson L, et al. The role of cholesterol metabolism and various steroid abnormalities in autism spectrum disorders: a hypothesis paper. Autism Res. 2017;10:1022–44. sourcePartly supported

  The Testosterone in Autism Spectrum Disorders section reports elevated fetal progesterone, testosterone, and cortisol in a study of males later diagnosed with ASD. The Vitamin D in Autism Spectrum Disorders section reports vitamin D deficiency in at least a subgroup. The Estrogens in Autism Spectrum Disorder section discusses estrogen-related genes and signaling, but does not establish abnormal estrogen levels; the paper also treats a common sterol-related mechanism as a hypothesis. The separate claim about decreased neuroactive steroids is attached to citation [11], not this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Individuals with Rett syndrome and the related CDKL5 disorder have elevated lipid levels.

“Individuals with Rett syndrome and the related CDKL5 disorder have elevated lipid levels [42, 43].”

• cites [42] Nagy G, Ackerman SL. Cholesterol metabolism and Rett syndrome pathogenesis. Nat Genet. 2013;45:965–7. sourceNot checked — no full text of the source
• cites [43] Pecorelli A, Belmonte G, Meloni G, Cervellati I, Gardi F, Sticozzi C, et al. Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder. Free Radic Biol Med. 2015;86:156–65. sourceSupported

May combine two claims.

Individuals with fragile X syndrome have low cholesterol, HDL, LDL, and ApoA1 levels, and their degree of maladaptive behaviors occurs in inverse relationship to cholesterol levels.

“Individuals with fragile X syndrome have low cholesterol, HDL, LDL, and ApoA1 levels [39–41], and their degree of maladaptive behaviors occurs in inverse relationship to cholesterol levels [40].”

• cites [39] Berry-Kravis E, et al. Cholesterol levels in fragile X syndrome. Am J Med Genet A. 2015;167A:379–84. sourcePartly supported

  The Results and Discussion report lower total cholesterol, HDL, and LDL in males with fragile X syndrome; findings in females were less definitive. Our copy does not report low ApoA1 or an inverse relationship between maladaptive-behavior severity and cholesterol levels. The latter claim is specifically attached to citation [40], but the paper's mention of behavioral symptoms does not establish that relationship. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [40] Çaku A, Seidah NG, Lortie A, Gagné N, Perron P, Dubé J, et al. New insights of altered lipid profile in fragile X syndrome. PLoS ONE. 2017;12:e0174301. sourceSupported
• cites [41] Lisik MZ, Gutmajster E, Sieroń AL. Low levels of HDL in fragile X syndrome patients. Lipids. 2016;51:189–92. sourcePartly supported

  The Results (page unavailable) report significantly lower HDL-C in males with fragile X syndrome, while total cholesterol and LDL-C did not differ statistically from controls. The paper does not report ApoA1 levels or an inverse relationship between maladaptive behavior and cholesterol; its Introduction describes behavior without linking it to cholesterol. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

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

The mammalian target of rapamycin pathway is affected by cholesterol homeostatic changes and is dysregulated in individuals with phosphatase and tensin homolog mutations, tuberous sclerosis, neurofibromatosis, fragile X syndrome, and Rett syndrome.

“Mammalian target of rapamycin pathway is affected by cholesterol homeostatic changes [37] and is dysregulated in individuals with phosphatase and tensin homolog mutations, tuberous sclerosis, neurofibromatosis, fragile X syndrome, and Rett syndrome [38].”

• cites [37] Xu J, Dang Y, Ren YR, Liu JO. Cholesterol trafficking is required for mTOR activation in endothelial cells. Proc Natl Acad Sci USA. 2010;107:4764–9. sourceNot checked — no full text of the source
• cites [38] Ganesan H, Balasubramanian V, Iyer M, Venugopal A, Subramaniam MD, Cho SG, et al. mTOR signalling pathway - A rootcause for idiopathic autism? BMB reports. 2019;52:424–33. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

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

Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency of 7-dehydrocholesterol reductase, the enzyme responsible for the last step of cholesterol biosynthesis, resulting from mutations in DHCR7.

“Smith–Lemli–Opitz syndrome (SLOS) is caused by the deficiency of 7-dehydrocholesterol (7DHC) reductase, the enzyme responsible for the last step of cholesterol biosynthesis [44], resulting from mutations in DHCR7 [45–47].”

• cites [44] Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 1993;341:1414. sourceNot checked — no full text of the source
• cites [45] Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik YK, Glossmann H, et al. Mutations in the 7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci USA. 1998;95:8181. sourceSupported
• cites [46] Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, et al. Mutations in the human sterol 7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998;63:55. sourcePartly supported

  The Abstract and Discussion identify DHCR7 as the gene encoding 7-dehydrocholesterol reductase and report mutations in three patients with SLOS. The Discussion concludes that DHCR7 mutations cause “at least some cases” and allows that milder cases may involve another gene; it does not establish the unqualified claim for all SLOS cases. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [47] Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, et al. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet. 1998;63:329. sourceSupported

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

All ApoA1 in the central nervous system traverses from the periphery.

“However, all ApoA1 in the CNS traverses from the periphery [19].”

• cites [19] Roheim PS, Carey M, Forte T, Vega GL. Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA. 1979;76:4646–9. sourcePartly supported

  The Results identify apo A-I in cerebrospinal fluid, and the Discussion considers transfer of apolipoproteins from plasma as a possibility. But the Discussion says the mechanisms can only be postulated and does not establish that all CNS apo A-I comes from the periphery. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Cholesterol reduction in neurons impairs synaptic vesicle exocytosis, neuronal activity, and neurotransmission and leads to dendritic spine and synapse degradation.

“Cholesterol reduction in neurons impairs synaptic vesicle exocytosis, neuronal activity, and neurotransmission and leads to dendritic spine and synapse degradation [20].”

• cites [20] Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6:254–64. sourceSupported

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

LPL variants are associated with neurite pathology and Alzheimer disease.

“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”

• cites [96] Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012;32:147–60. sourcePartly supported

  The “Proposed Functions of LPL in the Brain and CNS” section reports associations between some LPL variants and Alzheimer disease, while noting that findings on AD risk have been inconsistent. It also describes LPL’s role in neurite extension in cultured cells, but does not link LPL variants to neurite pathology. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [97] Gong H, Dong W, Rostad SW, Marcovina SM, Albers JJ, Brunzell JD, et al. Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer’s disease brains. J Histochem Cytochem. 2013;61:857–68. sourcePartly supported

  The Results (page unavailable) associate LPL immunostaining with neurite pathology in Alzheimer’s disease. The Discussion mentions a reported association between an LPL polymorphism and neurofibrillary tangle density in AD, but this paper does not establish that LPL variants are associated with neurite pathology or Alzheimer’s disease generally. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [98] Bruce D, Tang K, Reigan M. Genetic variants of lipoprotein lipase and regulatory factors associated with alzheimer’s disease risk. Int J Mol Sci. 2020;21:8338 sourceSupported

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

LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein.

“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”

• cites [96] Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012;32:147–60. sourceSupported
• cites [97] Gong H, Dong W, Rostad SW, Marcovina SM, Albers JJ, Brunzell JD, et al. Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer’s disease brains. J Histochem Cytochem. 2013;61:857–68. sourceSupported
• cites [98] Bruce D, Tang K, Reigan M. Genetic variants of lipoprotein lipase and regulatory factors associated with alzheimer’s disease risk. Int J Mol Sci. 2020;21:8338 sourceSupported

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

LPL is a regulator of brain energy balance.

“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”

• cites [96] Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012;32:147–60. sourceSupported
• cites [97] Gong H, Dong W, Rostad SW, Marcovina SM, Albers JJ, Brunzell JD, et al. Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer’s disease brains. J Histochem Cytochem. 2013;61:857–68. sourceSupported
• cites [98] Bruce D, Tang K, Reigan M. Genetic variants of lipoprotein lipase and regulatory factors associated with alzheimer’s disease risk. Int J Mol Sci. 2020;21:8338 sourceSupported

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

LPL is strongly expressed in the hypothalamus, hippocampus, and striatum.

“LPL hydrolyzes circulating chylomicrons and very-low-density lipoprotein, is a regulator of brain energy balance, is strongly expressed in the hypothalamus, hippocampus, and striatum, and LPL variants are associated with neurite pathology and Alzheimer disease [96–98].”

• cites [96] Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012;32:147–60. sourcePartly supported

  The section ‘LPL mRNA, Protein, and Enzyme Activity in Brain and CNS’ (page not provided) reports the highest LPL mRNA levels in the hippocampus and identifies LPL mRNA in striatal neurons. The energy-balance section confirms hypothalamic LPL expression, but the paper does not establish that expression is strong in the hypothalamus or striatum. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [97] Gong H, Dong W, Rostad SW, Marcovina SM, Albers JJ, Brunzell JD, et al. Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer’s disease brains. J Histochem Cytochem. 2013;61:857–68. sourcePartly supported

  The Results (page unavailable) report robust LPL staining in the hippocampal dentate gyrus and strong staining in striatal neurons. The passages do not report strong expression in the hypothalamus, so the three-region claim is only partly supported. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [98] Bruce D, Tang K, Reigan M. Genetic variants of lipoprotein lipase and regulatory factors associated with alzheimer’s disease risk. Int J Mol Sci. 2020;21:8338 sourcePartly supported

  Section 3, “LPL in the Central Nervous System” (page unavailable), reports LPL in hypothalamic neurons and increased expression in cultures of hypothalamus-derived astrocytes. It does not establish strong expression in the hypothalamus or identify the hippocampus and striatum as sites of strong expression. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

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

The occipital frontal head circumference is proportionately the smallest measurement at birth and is 2 standard deviations below the typical population.

“the occipital frontal head circumference (OFC) is proportionately the smallest measurement at birth and is 2 standard deviations (SD) below the typical population [50, 51].”

• cites [50] Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000;37:321–35. sourcePartly supported

  The Natural history section says head circumference is proportionately the smallest measurement at birth. It does not give a birth head-circumference value of exactly 2 SD below normal: it gives a range of −1 to −5 SD for most measurements in classical SLOS and a separate adult range. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [51] Lee RW, McGready J, Conley SK, Yanjanin NM, Nowaczyk MJ, Porter PD. Growth charts for individuals with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2012;158A:2707–13. sourcePartly supported

  The Results (Growth Parameters; page unavailable) report that mean OFC in individuals with Smith-Lemli-Opitz syndrome is about 2 standard deviations below the curve for age-matched typically developing children. The paper does not state that OFC is proportionately the smallest measurement at birth; it reports a similar approximate deficit for weight, height, and BMI. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

ANGPTL3 codes for a glycoprotein with roles in angiogenesis, tissue remodeling, inflammation, and inhibition of lipoprotein lipase (LPL) catalytic activity.

“which codes for a glycoprotein with roles in angiogenesis, tissue remodeling, inflammation, and inhibition of lipoprotein lipase (LPL) catalytic activity [93–95]”

• cites [93] Hato T, Tabata M, Oike Y. The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med. 2008;18:6–14. sourceNot checked — no full text of the source
• cites [94] Santulli G. Angiopoietin-like proteins: a comprehensive look. Front Endocrinol. 2014;5:4. sourcePartly supported

  The ANGPTL3 section states that ANGPTL3 inhibits LPL activity, and a reference listed in the paper reports that ANGPTL3 induces blood-vessel formation. The copy does not establish that ANGPTL3 is a glycoprotein or has roles in tissue remodeling or inflammation; its discussion of inflammation and glycoprotein status concerns other ANGPTL proteins. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [95] Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol. 2017;13:731–9. sourceCould not verify

  The available passages contain the paper’s title and bibliographic metadata, but no substantive text about ANGPTL3’s functions. Searches for angiogenesis, tissue remodeling, inflammation, and inhibition of lipoprotein lipase returned no passage that verifies the claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

May combine two claims. The quote only partly states this claim.

Individuals with low ApoB levels might have low lathosterol and desmosterol levels, as we detected in our subjects.

“Individuals with familial combined hyperlipidemia-1 have elevated levels of PCSK9 [102], lathosterol, and desmosterol [103], so individuals with low ApoB levels might have low lathosterol and desmosterol levels, as we detected in our subjects.”

• cites [102] Brouwers MC, Konrad RJ, van Himbergen TM, Isaacs A, Otokozawa S, Troutt JS, et al. Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia. Nutr Metab Cardiovasc Dis. 2013;23:1115–21. sourceNot checked — no full text of the source
• cites [103] van Himbergen TM, Otokozawa S, Matthan NR, Schaefer EJ, Buchsbaum A, Ai M, et al. Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway. Arterioscler Thromb Vasc Biol. 2010;30:113–20. sourcePartly supported

  The Results report elevated lathosterol in FCH patients and a correlation of both sterols with apoB. Desmosterol was significantly elevated in women with FCH, but not in men, so the unqualified statement that both sterols are elevated in individuals with FCH overstates the finding. The low-apoB statement is the citing authors’ inference, not a result established by this study. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

PCSK9 is important in regulation of lipoproteins and neuronal apoptosis.

“For example, PCSK9 is important in regulation of lipoproteins and neuronal apoptosis [101] and has abnormal function in individuals with fragile X syndrome [40, 97].”

• cites [101] Kysenius K, Muggalla P, Mätlik K, Arumäe U, Huttunen HJ. PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci. 2012;69:1903–16. sourceSupported

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

The lower adaptive impairment detected in the HDL <5thCent group might be related to decreased amounts of circulating miRNA.

“the lower adaptive impairment detected in the HDL <5thCent group might be related to decreased amounts of circulating miRNA.”

• cites [5] Vickers KC, Palmisano BT, Bassem S, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423. sourcePartly supported

  The Discussion (page unavailable) describes HDL as a possible carrier of circulating miRNAs, and the Results show that HDL can deliver miRNAs to cells. The paper does not examine people with HDL below the fifth centile, establish that they have less circulating miRNA, or link miRNA amounts to adaptive impairment. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

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

LPL is an autism candidate gene.

“LPL was identified as a gene affected in multiple hyperlipidemic conditions including familial combined hyperlipidemia [99] and is an autism candidate gene [100].”

• cites [100] Li J, Shi M, Ma Z, Zhao S, Euskirchen G, Ziskin J, et al. Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Mol Syst Biol. 2014;10:774. sourceCould not verify

  The Results section on DNA sequencing identifies LRP2—not LPL—as an autism spectrum disorder candidate gene. Searches for “LPL” and “lipoprotein lipase” found no passage in our copy addressing whether LPL is an autism candidate gene. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

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

PCSK9 has abnormal function in individuals with fragile X syndrome.

“For example, PCSK9 is important in regulation of lipoproteins and neuronal apoptosis [101] and has abnormal function in individuals with fragile X syndrome [40, 97].”

• cites [40] Çaku A, Seidah NG, Lortie A, Gagné N, Perron P, Dubé J, et al. New insights of altered lipid profile in fragile X syndrome. PLoS ONE. 2017;12:e0174301. sourceSupported
• cites [97] Gong H, Dong W, Rostad SW, Marcovina SM, Albers JJ, Brunzell JD, et al. Lipoprotein lipase (LPL) is associated with neurite pathology and its levels are markedly reduced in the dentate gyrus of Alzheimer’s disease brains. J Histochem Cytochem. 2013;61:857–68. sourceCould not verify

  The Results (page unavailable) concern lipoprotein lipase (LPL) in Alzheimer’s disease brains, not PCSK9 function in fragile X syndrome. Searches for “PCSK9 fragile X syndrome” and “proprotein convertase subtilisin kexin 9 fragile X FMR1” found no passage addressing the attributed claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

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

Findings of lipid abnormalities have been inconsistent in reported ASD studies.

“Findings of lipid abnormalities have been inconsistent in reported ASD studies [56–59, 64], although this might be partially due to varying dietary intake in countries where the studies were performed.”

• cites [56] Tierney E, Bukelis I, Thompson RE, Ahmed K, Aneja A, Kratz L, et al. Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:666–8. sourceCould not verify

  The Results report low cholesterol in 19 of 100 ASD samples, and the Discussion addresses possible explanations within this cohort. Neither passage compares lipid findings across reported ASD studies or says those findings have been inconsistent; searches for conflicting findings in previous studies found no such passage. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [57] Benachenhou S, Etcheverry A, Galarneau L, Dube J, Caku A. Implication of hypocholesterolemia in autism spectrum disorder and its associated comorbidities: a retrospective case-control study. Autism Res. 2019;12:1860–9. sourceNot checked — no full text of the source
• cites [58] Kim EK, Neggers YH, Shin CS, Kim E, Kim EM. Alterations in lipid profile of autistic boys: a case control study. Nutr Res. 2010;30:255–60. sourceNot checked — no full text of the source
• cites [59] Matsuzaki H, Iwata K, Suda S, Tsuchiya KJ, Suzuki K, Nakamura K, et al. Dyslipidemia in male patients with high-functioning autism. In: Poster presentation at the International Meeting for Autism Research 2010.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [64] Dziobek I, Gold SM, Wolf OT, Convit A. Hypercholesterolemia in Asperger syndrome: independence from lifestyle, obsessive-compulsive behavior, and social anxiety. Psychiatry Res. 2007;149:321. sourceNot checked — no full text of the source

May combine two claims.

Of the 5 subjects with elevated 7DHC, 2 had mildly increased 7DHC levels (0.39 and 0.45 μg/mL) without detectable 8DHC and cholesterol levels of 163.0 mg/dL and 300.0 mg/dL.

“Of the 5 subjects, 2 had mildly increased 7DHC levels (0.39 and 0.45 µg/mL) without detectable 8DHC and cholesterol levels of 163.0 mg/dL (Z-score + .21) and 300.0 mg/dL (Z-score +3.34), with the Z-score calculated using NHANES-III normally distributed cholesterol data.”

May combine two claims.

The HABL group (n=17) had a mean cholesterol level of 80 mg/dL and a mean OFC at the 83rd centile.

“Furthermore, the HABL group (n = 17), with a mean cholesterol level of 80 mg/dL, had a mean OFC at the 83rd centile.”

May combine two claims.

The fourth subject had a 7DHC level of 0.75 μg/mL, a trace unquantifiable level of 8DHC, and cholesterol 164.4 mg/dL.

“The fourth subject had a 7DHC level of 0.75 µg/mL, a trace, unquantifiable level of 8DHC, and a cholesterol level 164.4 mg/dL (Z-score +0.25).”

The quote only partly states this claim.

There were no significant differences in M:F ratio between HDL, ApoA1, and ApoB <5thCent and ≥5thCent groups.

“There were no significant differences in the M:F ratio with the HDL, ApoA1, and ApoB groups.”

May combine two claims.

The HABL group had lower scores in Communication, Daily Living Skills, and Socialization.

“The HABL group had lower scores in Communication (p = 0.033; BHC p = 0.044), Daily Living Skills (p = 0.002; BHC p = 0.003), and Socialization (p = 0.002; BHC p = 0.003).”

May combine two claims.

The HABL group had lower ApoA1 levels and centiles than the HAL group.

“The HABL group also had lower ApoA1 levels and centiles (mean of 83 mg/dL with 3 measurements assigned the value of 19 mg/dL, mean centile 1.1) than the HAL group (mean of 97 mg/dL with no measures below assay, mean centile 1.9), so there may be a threshold effect with ApoA1 levels that leads to ASD symptoms since ApoA1 has multiple roles within the CNS and has been implicated in numerous”

May combine two claims.

There were no significant results for OFC, height, weight centiles, and BMI between lipid groups, although there was a trend toward significance for ApoB <5thCent having lower BMI.

“There were no significant results, although there was a trend toward significance of ApoB <5thCent (n = 12) having a lower BMI (p = 0.006; BHC p = 0.095) (Supplementary Table 16).”

May combine two claims.

ASD subjects had the highest percentage of HABL (AGRE 26%, NIH 4%, NHANES-III-SWEP 6%) and HAL (AGRE 19%, NIH 12%, NHANES-III-SWEP 11%).

“The ASD subjects had the highest percentage of HABL (AGRE 26%, NIH 4%, NHANES-III-SWEP 6%) and HAL (AGRE 19%, NIH 12%, NHANES-III-SWEP 11%), while the typically developing children had the highest percentage of HBL (AGRE 25%, NIH 67%, NHANES-III-SWEP 38%).”

May combine two claims.

In AGRE subjects, 22.1% had ApoB levels <5thCent, a 4.4-fold increase.

“We detected elevations in the number of individuals with levels <5thCent: cholesterol 23.0% (4.6-fold increase), HDL 31.6% (6.3-fold increase), ApoA1 16.9% (3.4-fold increase), and ApoB 22.1% (4.4-fold increase).”

May combine two claims.

In AGRE subjects, 31.6% had HDL levels <5thCent, a 6.3-fold increase.

“We detected elevations in the number of individuals with levels <5thCent: cholesterol 23.0% (4.6-fold increase), HDL 31.6% (6.3-fold increase), ApoA1 16.9% (3.4-fold increase), and ApoB 22.1% (4.4-fold increase).”

May combine two claims.

The HABL group had lower cholesterol levels and centiles than HAL and HBL groups.

“However, in analyses of the subset of subjects who had apolipoprotein testing and Vineland scores, the HABL subjects demonstrated more impairment in adaptive functioning than the rest of the subjects and this might have been related to their lower cholesterol levels and centiles (mean of 78 mg/dL, plus 3 cholesterol measurements below what the assay could measure and assigned the value 50 mg/dL,”

May combine two claims.

Of 367 AGRE subjects, 17% had ApoA1 <5thCent and 22% had ApoB <5thCent.

“Of the 367 AGRE subjects, 17% had ApoA1 <5thCent and 22% had ApoB <5thCent, and we organized the subjects into apolipoprotein groups: combined hypolipidemia (HABL) (ApoA1 <5thCent, ApoB <5thCent): 34 (28 M, 6 F) (9% of subjects); hypoalphalipoproteinemia (HAL) (ApoA1 <5thCent, ApoB ≥5thCent): 28 (23 M, 5 F) (8%); hypobetalipoproteinemia (HBL) (ApoA1 ≥5thCent, ApoB <5thCent): 47 (35 M, 12 F) (13%);”

May combine two claims.

Kruskal-Wallis-BHC of Vineland-ABC with HDL and ApoA1 groups trended toward but did not reach statistical significance, likely due to smaller number of subjects.

“The Kruskal-Wallis–BHC of Vineland-ABC with the HDL and ApoA1 <5thCent&≥5thCent-groups trended toward but did not reach statistical significance, which was likely secondary to the smaller number of subjects (all subjects n = 286, 7DHC tested n = 37).”

May combine two claims.

A third subject had a 7DHC level of 0.52 μg/mL, an unquantifiable trace amount of 8DHC, and a cholesterol level of 96 (Z-score −1.31).

“A third subject had a 7DHC level of 0.52 µg/mL, an unquantifiable trace amount of 8DHC, and a cholesterol level of 96 (Z-score −1.31).”

May combine two claims.

The fifth subject had a 7DHC level of 1.31 μg/mL, an unquantifiable level of 8DHC, and cholesterol 238.6 mg/dL.

“The fifth subject had a 7DHC level of 1.31 µg/mL, an unquantifiable level of 8DHC, and a cholesterol level of 238.6 mg/dL (Z-score +1.94).”

May combine two claims.

The AGRE subjects with cholesterol <5thCent had a mean cholesterol of 96 mg/dL and the analysis of Vineland-ABC differences between cholesterol groups was not significant.

“The AGRE subjects with cholesterol <5thCent had a mean cholesterol of 96 mg/dL and the analysis of the differences in the Vineland-ABC scores between the cholesterol <5thCent&≥5thCent-groups was not significant.”

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

The third subject was treated with trazodone and buspirone 2 years after blood sample.

“At the time of medical history completion, 2 years after AGRE obtained the blood sample, that subject was treated with trazodone and buspirone medications, which are known to increase 7DHC levels in individuals without SLOS [84, 85].”

May combine two claims.

The adaptive skill deficits in the HABL group do not appear related to low blood HDL levels, since the HABL group had a higher mean HDL centile than the HAL group and the HAL group did not have adaptive functioning deficits.

“However, the adaptive skill deficits in the HABL group do not appear related to low blood HDL levels, since the HABL group had a higher mean HDL centile than the HAL group and the HAL group did not have adaptive functioning deficits.”

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

Mutations in genes that alter synaptic function can also lead to intellectual disability and ASD.

“Mutations in genes that alter synaptic function can also lead to intellectual disability and ASD [36].”

• cites [36] Bourgeron T. A synaptic trek to autism. Curr Opin Neurobiol. 2009;19:231–4. sourceNot checked — no full text of the source

May combine two claims.

No subject had a finding consistent with SLOS or other disorders of post-squalene cholesterol synthesis, confirming that SLOS is rare within ASD in the absence of cardinal clinical features.

“Despite the increased percentage with hypocholesterolemia, no subject had a finding consistent with SLOS or other disorders of post-squalene cholesterol synthesis, confirming that SLOS is rare within ASD in the absence of cardinal clinical features.”

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

No measurement exceeded the upper limits of the assays at KKI or NIH.

“No measurement exceeded the upper limits of the assays at KKI or NIH.”

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

The modestly increased lathosterol levels could reflect extreme of normal or transient increase in cholesterol synthesis.

“Three subjects had modestly increased lathosterol levels (between 3.08 and 4.32 µg/mL), which could reflect the extreme of normal or a transient increase in the rate of cholesterol synthesis, e.g., recovery from infection.”

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

A deficit of ApoA1 in the periphery suggests that a deficit could exist in the CNS as well, because the brain is dependent upon ApoA1 being transported from the periphery to the CNS.

“The brain is dependent upon ApoA1 being transported from the periphery to the CNS, so a deficit of ApoA1 in the periphery suggests that a deficit could exist in the CNS as well.”

• AssumptionRests on an assumption: ApoA1 is the primary protein constituent of HDL.
• AssumptionRests on an assumption: The brain is dependent upon ApoA1 being transported from the periphery to the CNS.

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

The study was performed in compliance with the Declaration of Helsinki and standards established by the Institutional Review Boards of AGRE, Johns Hopkins Medicine, and NIH.

“We performed the study in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and standards established by the Institutional Review Boards of AGRE, Johns Hopkins Medicine, and the National Institutes of Health (NIH).”

May combine two claims.

The low lathosterol with cholesterol centiles ≤2 indicates a low rate of sterol synthesis, a recognized common cause of low lathosterol.

“Of the 5 subjects with lathosterol levels lower than the reference range, all had cholesterol centiles ≤2, indicating a low rate of sterol synthesis, a recognized, common cause of a low lathosterol level.”

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

Informed consent was obtained from all participants except those whose de-identified NHANES-III data were used.

“Informed consent was not required to use the NHANES-III data, which are de-identified and available for download at the Centers for Disease Control (CDC)’s website. Informed consent was obtained from all other participants, with the consent process performed by investigators of AGRE or the NIH.”

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

The complex regulation of lipid gene expression in the periphery could differ from regulation of the same genes in the CNS.

“In addition, the complex regulation of lipid gene expression in the periphery could differ from regulation of the same genes in the CNS.”

• AssumptionRests on an assumption: The complex regulation of lipid gene expression in the periphery could differ from regulation of the same genes in the CNS.

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

For 86 subjects with cholesterol measured at both KKI and NIH, the NIH cholesterol mean was 101.28 ± 41.0 mg/dL and the KKI cholesterol mean was 136.51 ± 43.22 mg/dL, and NIH-derived values were used for most statistical analyses.

“For the 86 subjects who had cholesterol levels performed at both KKI and NIH, the NIH cholesterol mean and SD was 101.28 ± 41.0 mg/dL, while the KKI cholesterol mean was 136.51 ± 43.22 mg/dL, and the NIH-derived level values were used for most of the statistical analyses.”

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

No attempts were made to replicate the sterol and lipid testing results.

“No attempts were made to replicate the sterol and lipid testing results.”

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

AGRE arranged fragile X gene testing in a CLIA-certified laboratory for 407 subjects, and for remaining subjects had fragile X testing performed for a sibling; no subject or sibling had a fragile X pre-mutation or full mutation.

“AGRE arranged for fragile X gene testing in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for 407 subjects, and, for the remaining subjects, AGRE had fragile X testing performed for a sibling with either autism, not quite autism, or broad spectrum. No subject or sibling had a fragile X pre-mutation or full mutation.”

May combine two claims.

Individuals with severe SLOS have reduced levels of alpha-apolipoprotein than individuals with mild SLOS and significantly less alpha-apolipoprotein than an age-matched typical control group.

“Individuals with severe SLOS have reduced levels of alpha-apolipoprotein (defined as ApoA1 and ApoA without subclassification) than individuals with mild SLOS and significantly less alpha-apolipoprotein than an age-matched typical control group.”

• cites [54] Behúlová D, Bzdúch V, Skodová J, Dello Russo A, Corso G.Ponec J, et al. Serum lipids and apolipoproteins in children with the Smith-Lemli-Opitz syndrome. J Inherit Metab Dis. 2000;23:413–5. sourceNot checked — no full text of the source
• cites [55] Oláh AV, Szabó GP, Varga J, Balogh L, Csábi G, Csákváry V, et al. Relation between biomarkers and clinical severity in patients with Smith-Lemli-Opitz syndrome. Eur J Pediatrics. 2013;172:623–30. sourceNot checked — no full text of the source

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

The observed peak in lipid levels at age 15.0-16.9 years could indicate ASD-related lipid dysregulation related to puberty, but data may be skewed by small numbers.

“Although we observed a peak in the 4 lipid levels during age 15.0–16.9 years that could indicate ASD-related lipid dysregulation related to puberty, the data may have been skewed due to the small number of subjects in that interval.”

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

APOA1 gene variants could decrease ApoA1 levels in the CNS and present with low ApoA1 as a biomarker in blood.

“For example, APOA1 gene variants could decrease ApoA1 levels in the CNS and present with low ApoA1 as a biomarker in blood.”

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

Because fasting status was not recorded, triglyceride measurements and calculated LDL levels were not used.

“Because the fasting status of the subjects were not recorded, triglyceride measurements and calculated LDL levels were not used.”

May combine two claims.

Unrecognized SLOS probably represents <0.7% of ASD and more likely <0.2%.

“The fact that no SLOS was identified indicates that unrecognized SLOS probably represents <0.7% of ASD and more likely <0.2%.”

May combine two claims.

While biochemically mild SLOS cannot be excluded for samples with increased 8DHC, other possibilities include carrier status or medication effect, with medication effect most likely in this population.

“While biochemically mild forms of SLOS cannot be excluded for the samples with increased 8DHC levels, other possibilities include carrier status for SLOS or medication effect, with the latter being the most likely in our subject population.”

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

Below-assay values were assigned the bottom of the assay range: 6 cholesterol values 50 mg/dL, 6 HDL 3 mg/dL, 3 ApoA1 19 mg/dL, and 8 ApoB 26 mg/dL.

“The following numbers of subjects had levels below what could be measured by the analyzer at NIH (were “below assay”) and were assigned a value at the bottom assay’s range: 6 cholesterol values were assigned 50 mg/dL; 6 HDL were assigned 3 mg/dL; 3 ApoA1 were assigned 19 mg/dL; and 8 ApoB were assigned 26 mg/dL.”

May combine two claims.

Age and sex were not directly controlled between the AGRE and NIH groups, but age- and sex-specific percentiles derived from NHANES-III were used, so the analyses did control for age and sex.

“Age and sex were not directly controlled between the AGRE and NIH groups. However, age- and sex-specific percentiles were derived from NHANES-III and were used for analysis of the lipid levels in the groups of individuals with ASD and typically developing individuals. Thus, the analyses did control for the variables of age and sex.”

May combine two claims.

ASD is frequently observed in SLOS; however, the rate of ASD clinical diagnosis appears to be artificially increased due to lower cognitive function.

“ASD is frequently observed in SLOS [52, 53]; however, the rate of ASD clinical diagnosis appears to be artificially increased due to lower cognitive function.”

• cites [52] Tierney E, Nwokoro NA, Porter FD, Freund LS, Ghuman JK, Kelley RI, et al. Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet. 2001;98:191–200. sourceNot checked — no full text of the source
• cites [53] Sikora DM, Pettit-Kekel K, Penfield J, Merkens LS, Steiner RD. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2006;140:1511–8. sourceNot checked — no full text of the source

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

The blood samples were often obtained from the children at different ages than the physical exams, medical interviews, and behavioral forms.

“(7) the blood samples were often obtained from the children at different ages than the physical exams, medical interviews, and behavioral forms;”

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

Prior studies have shown abnormal lipid levels in individuals with ASD.

“While prior studies have shown abnormal lipid levels in individuals with ASD, we present new evidence for a disorder of cholesterol homeostasis in ASD other than SLOS.”

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

The samples were from multiplex families so we cannot extrapolate as to the degree of sterol and lipid abnormalities in subjects from simplex ASD families.

“(8) the samples were from multiplex families so we cannot extrapolate as to the degree of sterol and lipid abnormalities in subjects from simplex ASD families.”

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

We had limited clinical information about diet, medications, and supplements that were being taken at the time of the blood draw, as well as other conditions, such as chronic diarrhea that could underlie the abnormal lipid pattern detected in our subjects or contribute to elevated 7DHC plus 8DHC levels.

“(4) we had limited clinical information about diet, medications, and supplements that were being taken at the time of the blood draw, as well as other conditions, such as chronic diarrhea that could underlie the abnormal lipid pattern detected in our subjects or contribute to elevated 7DHC plus 8DHC levels;”

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

Analyses were performed only on blood samples, while lipid metabolism and regulation are different in the periphery than in the CNS.

“(6) analyses were performed only on blood samples, while lipid metabolism and regulation are different in the periphery than in the CNS;”

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

We had limited physical parameter information to be able to determine whether there are unique physical characteristics to individuals with lipid levels <5thCent and to be able to determine whether two subjects who had both elevated 7DHC and 8DHC levels had physical features of SLOS.

“(5) we had limited physical parameter information to be able to determine whether there are unique physical characteristics to individuals with lipid levels <5thCent and to be able to determine whether two subjects who had both elevated 7DHC and 8DHC levels had physical features of SLOS;”

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

Gain-of-function gene variants of PCSK9 occur with familial combined hypercholesterolemia, in which individuals have increases in plasma total cholesterol, ApoB, and/or triglyceride levels.

“Gain-of-function gene variants of PCSK9 occur with familial combined hypercholesterolemia, in which individuals have increases in plasma total cholesterol, ApoB, and/or triglyceride levels, while loss-of-function variants occur with familial hypobetalipoproteinemia-1.”

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

LPL was identified as a gene affected in multiple hyperlipidemic conditions including familial combined hyperlipidemia.

“LPL was identified as a gene affected in multiple hyperlipidemic conditions including familial combined hyperlipidemia [99] and is an autism candidate gene [100].”

• cites [99] Online Mendelian Inheritace in Man. 144250, Hyperlipidemia, familial combined, 3; FCHL3. Baltimore, MD: Johns Hopkins University; 1986.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

We lacked information regarding parental lipoprotein profiles, which could help identify inherited lipoprotein conditions.

“(2) we lacked information regarding parental lipoprotein profiles, which could help identify inherited lipoprotein conditions;”

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

The subjects were not fasting at the time of the blood draws so we could not perform triglyceride analyses or calculate the LDL levels using a triglyceride-dependent formula.

“(3) the subjects were not fasting at the time of the blood draws so we could not perform triglyceride analyses or calculate the LDL levels using a triglyceride-dependent formula;”

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

7DHC was not quantified in all samples.

“Limitations include that (1) 7DHC was not quantified in all samples;”

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

Loss-of-function variants of PCSK9 occur with familial hypobetalipoproteinemia-1.

“Gain-of-function gene variants of PCSK9 occur with familial combined hypercholesterolemia, in which individuals have increases in plasma total cholesterol, ApoB, and/or triglyceride levels, while loss-of-function variants occur with familial hypobetalipoproteinemia-1.”