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Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Angela J. Villar, Charles J. Epstein
Smith-Lemli-Opitz (SLO) syndrome, which is caused by mutations in the sterol delta-7-reductase gene (DHCR7), is a serious inherited disorder that results in an inability to synthesize enough cholesterol to support normal growth and development. This results in mental retardation and physical abnormalities such as, microcephaly, growth retardation, hypoplastic external genitalia, characteristic facies with micrognathia and anteverted nostrils.
Orthogenomics
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Joseph R. Veltmann, Roberta L. Kline
This patient’s test results from a commercial genomic testing company showed gene variants for DHCR7, GC and VDR Fokl. The interpretative lab report informs us that he cannot effectively convert sunshine into vitamin D, transport of vitamin D and its metabolites is impaired, and binding of the active metabolite to the vitamin D receptor in the nucleus is also compromised. The latter is particularly important, since vitamin D acts through its vitamin D receptor to influence cell types and tissues important in OA – chondrocytes, osteoclasts and osteoblasts (54). The appropriate intervention for this OA patient is to encourage the consumption of vitamin D-rich foods and/or supplement with a vitamin D/K2 emulsion. His genomic test report also provides relevant biomarker testing recommendations. Monitoring his response to these interventions by testing both the 25-hydroxy and the 1,alpha 25-dihydroxy forms of vitamin D would be important for this patient.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Differential diagnosis: stippling may be a feature of many disorders, which include chondrodysplasia punctata (p. 272); warfarin embryopathy (p. 294); fetal exposure to hydantoin and alcohol; trisomy 18 (p. 586); trisomy 21. CHILD syndrome: an acronym for Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects, a very rare condition which shows unilateral involvement with joint contractures, limb hypoplasia and a wide range of organ malformations (cardiac, genitourinary, endocrine, cerebral); Zellweger syndrome (p. 301); mucolipidosis type 2 (I-cell disease) (p. 381); GM gangliosidosis type 1 – findings are similar to I-cell disease and it is also a storage disorder; Cornelia de Lange syndrome (p. 454); Sjogren syndrome; multiple sulphatase deficiency, a recessive condition caused by mutations in the sulphatase-modifying factor-1 gene (SUMF1), responsible for the activation of all the sulphatase enzymes in the cell. Smith-Lemli-Opitz syndrome – caused by a defect in the enzyme 3 beta-hydroxysterol-delta 7-reductase; this converts 7-dehydrocholesterol to cholesterol (gene DHCR7). This more complex syndrome has characteristic facial traits (bitemporal narrowing, ptosis, broad nasal bridge, short nasal root, anteverted nares, micrognathia), cleft palate, brain anomalies (microcephaly, agenesis of the corpus callo-sum, holoprosencephaly), and anomalies of genital, cardiovascular and gastrointestinal systems. Skeletal anomalies include rhizomelia, postaxial polydactyly, syndactyly of second and third toes and short, proximally placed thumbs.
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
Smith-Lemli-Opitz (SLO) is a recessively inherited multiple malformation syndrome caused by mutations in DHCR7 leading to deficiency of 7dehydrocholesterol reductase [146]. Fetal hydrops has been reported, possibly related to fetal akinesia (and lymphatic stasis) [147,148]. Individuals with SLO typically have microcephaly, characteristic facial dysmorphism, polydactyly, intellectual disability and autistic spectrum disorder [146,149].
Silver nanoparticle-induced expression of proteins related to oxidative stress and neurodegeneration in an in vitro human blood-brain barrier model
Published in Nanotoxicology, 2019
Asif Manzoor Khan, Barbara Korzeniowska, Vladimir Gorshkov, Muhammad Tahir, Henrik Schrøder, Lilian Skytte, Kaare Lund Rasmussen, Surabhi Khandige, Jakob Møller-Jensen, Frank Kjeldsen
Other pathways affected by AgNPs exposure were the cholesterol biosynthesis and lipid homeostasis pathways, which were both upregulated. Upregulation of these pathways has been associated with Alzheimer’s disease (AD) and other neurodegenerative diseases. It has been reported that cholesterol levels constantly increase during the clinical progression of Alzheimer’s disease (Zhang and Liu 2015; Cutler et al. 2004). The upregulation of 7-dehydrocholesterol reductase (DHCR7), an important enzyme in cholesterol synthesis, leads to increased production of cholesterol and alterations in cholesterol metabolism, leading to various brain diseases (Zhang et al. 2018; Hughes et al. 2013; Witsch-Baumgartner, Loffler, and Utermann 2001). Cellular exposure to AgNPs induces increased turnover of DHCR7, which in turn deregulates cholesterol metabolism (Goedeke and Fernandez-Hernando 2014). This suggests that AgNPs exposure may result in activation of similar pathways to those active pathways reported under conditions of neurotoxicity and neurodegeneration. Other proteins affected by AgNPs exposure is that of ABC (ATP-binding cassette) transporters involved in lipid homeostasis. Human ABC transporters are found in different cell types including the endothelial cells of the BBB and brain parenchymal cells. They transport molecules across lipid membranes and mediate a critical role in cellular homeostasis (TER Beek, Guskov, and Slotboom 2014; Abuznait and Kaddoumi 2012). In many recent studies, ABC transporters have been implicated in several CNS and non-CNS related diseases (Abuznait and Kaddoumi 2012; Pereira et al. 2018; Weiss et al. 2009). Alteration in the expression and functional activity of ABC transporters may contribute to the aggregation of amyloid β-peptide (Aβ) in the brain and/or endothelial cells, leading to increased risk of developing AD by failure to protect the BBB (Nicolazzo and Mehta 2010; Abuznait et al. 2011; Rapposelli, Digiacomo, and Balsamo 2009). In this context, we may add that AgNPs-induced toxicity alters the level of the ABC transporters in the BBB, which can in turn be a risk factor for neurodegenerative diseases.
Association between altered lipid profiles and attention deficit hyperactivity disorder in boys
Published in Nordic Journal of Psychiatry, 2018
Changes in the lipid profile might be related to the structural and functional brain changes reported in ADHD patients. Cholesterol has significant interactions with proteins, which control embryonic development, and plays an important role in developmental pathways such as the SHH pathway, which has a role in formation of the brain. The SHH is a morphogen involved in the patterning of the nervous system and limbs, together with other transcription factors and secreted proteins [50]. The SHH is covalently modified with both palmitate and cholesterol and secreted as part of a lipoprotein complex that regulates brain morphogenesis through the patched/smoothened signaling system, during embryonic development. It is secreted from the notochord and ventral floor plate cells and forms a concentration gradient along the entire dorsal-ventral axis. Following covalent modification by cholesterol, the post-translational effect of the SHH is the establishment of a morphogenic SHH concentration gradient that moves from high ventral concentration to low dorsal region concentration. Intracellular cell signaling systems are affected by variations in the SHH gradient, which ultimately determine the expression of future cell types by the sequential induction of transcription factors in ventra progenitor cells [51]. One determinant of the eventual structure of the maturing brain is the formation of discrete cell precursor domains in the neural tube as a result of the SHH morphogenic front [52]. Experimental studies have shown that during late embryonic and postnatal brain development, SHH signaling regulates neural precursor and stem cell proliferation in dorsal neocortical, hippocampal, tectal, and cerebellar regions [53]. A loss of SHH processing in humans can result in the failure of midline brain structures to form appropriately, as evidenced in holoprosencephaly [54]. In patients with Smith–Lemli–Opitz syndrome (SLOS), which is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7), the most common neuroimaging abnormality has been reported to be incomplete formation of midline structures including the corpus callosum and cerebellum [55]. Of note, one of the most common neuroimaging abnormalities in ADHD is a reduction in the corpus callosum and cerebellum size, which supports the aberrant connectivity hypothesis that ADHD is a disorder of connectivity, involving inter- and intrahemispheric communications with possible alterations of intracortical connections [56]. In both ADHD and SLOS, it is not known whether callosal hypoplasia results from a primary patterning defect or later dysfunction of neuronal cortical connectivity and axonal migration, or both.