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Forbes D. Porter - One of the best experts on this subject based on the ideXlab platform.
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smith lemli Opitz Syndrome pathogenesis diagnosis and management
European Journal of Human Genetics, 2008Co-Authors: Forbes D. PorterAbstract:Smith-Lemli-Opitz Syndrome (SLOS) is a malformation Syndrome due to a deficiency of 7-dehydrocholesterol reductase (DHCR7). DHCR7 primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS.
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Smith–Lemli–Opitz Syndrome: pathogenesis, diagnosis and management
European Journal of Human Genetics, 2008Co-Authors: Forbes D. PorterAbstract:Smith–Lemli–Opitz Syndrome (SLOS) is a malformation Syndrome due to a deficiency of 7-dehydrocholesterol reductase (DHCR7). DHCR7 primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS.
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3β hydroxysterol δ7 reductase and the smith lemli Opitz Syndrome
Molecular Genetics and Metabolism, 2005Co-Authors: Lina S Correacerro, Forbes D. PorterAbstract:In the final step of cholesterol synthesis, 7-dehydrocholesterol reductase (DHCR7) reduces the double bond at C7-8 of 7-dehydrocholesterol to yield cholesterol. Mutations of DHCR7 cause Smith-Lemli-Opitz Syndrome (SLOS). Over 100 different mutations of DHCR7 have been identified in SLOS patients. SLOS is a classical multiple malformation, mental retardation Syndrome, and was the first human malformation Syndrome shown to result from an inborn error of cholesterol synthesis. This paper reviews the biochemical, molecular, and mutational aspects of DHCR7.
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3β-Hydroxysterol Δ7-reductase and the Smith–Lemli–Opitz Syndrome
Molecular genetics and metabolism, 2004Co-Authors: Lina S. Correa-cerro, Forbes D. PorterAbstract:In the final step of cholesterol synthesis, 7-dehydrocholesterol reductase (DHCR7) reduces the double bond at C7-8 of 7-dehydrocholesterol to yield cholesterol. Mutations of DHCR7 cause Smith-Lemli-Opitz Syndrome (SLOS). Over 100 different mutations of DHCR7 have been identified in SLOS patients. SLOS is a classical multiple malformation, mental retardation Syndrome, and was the first human malformation Syndrome shown to result from an inborn error of cholesterol synthesis. This paper reviews the biochemical, molecular, and mutational aspects of DHCR7.
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Cholesterol metabolism and suicidality in Smith-Lemli-Opitz Syndrome carriers.
The American journal of psychiatry, 2004Co-Authors: Aleksandra Lalovic, Louise S. Merkens, Laura Russell, Genevieve Arsenault-lapierre, Małgorzata J.m. Nowaczyk, Forbes D. Porter, Robert D. Steiner, Gustavo TureckiAbstract:OBJECTIVE: The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz Syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. METHOD: Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz Syndrome and 54 matched comparison subjects. RESULTS: There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz Syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz Syndrome carriers than among the comparison subjects. CONCLUSIONS: These results, based on a unique study design, provide add...
Amy Dobson - One of the best experts on this subject based on the ideXlab platform.
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Clinical management of patients with ASXL1 mutations and Bohring-Opitz Syndrome, emphasizing the need for Wilms tumor surveillance.
American journal of medical genetics. Part A, 2015Co-Authors: Bianca Russell, Wen-hann Tan, Jennifer J Johnston, Leslie G Biesecker, Nancy Kramer, Angela Pickart, William Rhead, Catherine A Brownstein, L Kate Clarkson, Amy DobsonAbstract:Bohring-Opitz Syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz Syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz Syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
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Clinical management of patients with ASXL1 mutations and Bohring–Opitz Syndrome, emphasizing the need for Wilms tumor surveillance
American Journal of Medical Genetics Part A, 2015Co-Authors: Bianca Russell, Wen-hann Tan, Jennifer J Johnston, Leslie G Biesecker, Nancy Kramer, Angela Pickart, William Rhead, Catherine A Brownstein, L. Kate Clarkson, Amy DobsonAbstract:Bohring-Opitz Syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz Syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz Syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
Bianca Russell - One of the best experts on this subject based on the ideXlab platform.
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Clinical management of patients with ASXL1 mutations and Bohring–Opitz Syndrome, emphasizing the need for Wilms tumor surveillance
American Journal of Medical Genetics Part A, 2015Co-Authors: Bianca Russell, Wen-hann Tan, Jennifer J Johnston, Leslie G Biesecker, Nancy Kramer, Angela Pickart, William Rhead, Catherine A Brownstein, L. Kate Clarkson, Amy DobsonAbstract:Bohring-Opitz Syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz Syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz Syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
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Clinical management of patients with ASXL1 mutations and Bohring-Opitz Syndrome, emphasizing the need for Wilms tumor surveillance.
American journal of medical genetics. Part A, 2015Co-Authors: Bianca Russell, Wen-hann Tan, Jennifer J Johnston, Leslie G Biesecker, Nancy Kramer, Angela Pickart, William Rhead, Catherine A Brownstein, L Kate Clarkson, Amy DobsonAbstract:Bohring-Opitz Syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz Syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz Syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
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Bohring-Opitz Syndrome
1993Co-Authors: Bianca Russell, Wen-hann Tan, John M. GrahamAbstract:Clinical characteristics Bohring-Opitz Syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus ( simplex ), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted. Diagnosis/testing The diagnosis of Bohring-Opitz Syndrome (BOS) is established in a proband with suggestive clinical features and/or the identification of a constitutional heterozygous pathogenic variant in ASXL1 by molecular genetic testing. Management Treatment of manifestations. Cyclic vomiting may be managed by identification and avoidance of triggers, daily maintenance medication, and early abortive treatment; G-tubes or GJ-tubes may decrease aspiration and improve nutrition. Due to the prevalence of obstructive sleep apnea, polysomnography should be considered. Referral to a craniofacial team should be considered for those with palatal abnormalities, micrognathia, or obstructive sleep apnea. Tracheostomy may be considered for those with recurrent aspiration who develop secondary lung disease, or in those with severe sleep apnea that is not adequately treated with noninvasive pressure support (e.g., CPAP, BiPAP) or surgical intervention (e.g., mandibular distraction). Standard management is indicated for seizures, congenital heart defects, intellectual disability, myopia, urinary tract infections, urinary retention, and renal stones. Prevention of primary manifestations. Adequate treatment of severe emesis can decrease hospitalizations, infectious exposures, and ascending aspiration. Surveillance: Renal ultrasound every three months from birth to age eight to screen for the development of Wilms tumor; frequent monitoring of growth and development; close monitoring of feeding intolerance with a gastroenterology specialist; regular follow up for vision optimization. Agents/circumstances to avoid. Triggers for vomiting should be avoided and managed with prophylactic antiemetics prior to the exposure. Genetic counseling Bohring-Opitz Syndrome (BOS) is typically the result of a de novo pathogenic variant in ASXL1. When BOS results from a de novo variant, the risk to the sibs of a proband is small. No individuals with BOS have been reported to reproduce. Although the vast majority of BOS occurs as the result of a de novo variant in ASXL1, molecular genetic testing can be used to evaluate a pregnancy at theoretically increased risk as a result of constitutional and/or germline mosaicism for an ASXL1 pathogenic variant in a clinically unaffected parent.
Robert D. Steiner - One of the best experts on this subject based on the ideXlab platform.
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Smith–Lemli–Opitz Syndrome
Encyclopedia of the Neurological Sciences, 2014Co-Authors: Melissa D. Svoboda, E. Finanger, Robert D. SteinerAbstract:Smith–Lemli–Opitz Syndrome (SLOS) is an autosomal recessive congenital malformation Syndrome due to a defect in the enzyme 7-dehydrocholesterol reductase. This enzyme is critical in cholesterol biosynthesis, and the resulting defect causes decreased cholesterol production and an increase in the potentially toxic cholesterol precursors, 7- and 8-dehydrocholesterol. The clinical phenotype encompasses a wide spectrum. This article provides a brief overview of SLOS including clinical features, diagnosis, current therapy, and future potential therapies.
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Challenging Behavior in Smith-Lemli-Opitz Syndrome: Initial Test of Biobehavioral Influences
Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology, 2013Co-Authors: Kurt A. Freeman, Louise S. Merkens, Rose F. Eagle, Darryn M. Sikora, Kersti Pettit-kekel, Mina Nguyen-driver, Robert D. SteinerAbstract:Objective:To study challenging behavior (destruction, aggression, self-injury, stereotypy) in children with Smith-Lemli-Opitz Syndrome (SLOS) using a biobehavioral model that helps distinguish biological from socially mediated variables influencing the behavior.Background:SLOS is an autosomal-recess
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Smith–Lemli–Opitz Syndrome
Expert reviews in molecular medicine, 2011Co-Authors: Andrea E. Debarber, Louise S. Merkens, Yasemen Eroglu, Anuradha S. Pappu, Robert D. SteinerAbstract:Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability Syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency Syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.
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smith lemli Opitz Syndrome
Expert Reviews in Molecular Medicine, 2011Co-Authors: Andrea E. Debarber, Louise S. Merkens, Yasemen Eroglu, Anuradha S. Pappu, Robert D. SteinerAbstract:Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability Syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency Syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.
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Cholesterol metabolism and suicidality in Smith-Lemli-Opitz Syndrome carriers.
The American journal of psychiatry, 2004Co-Authors: Aleksandra Lalovic, Louise S. Merkens, Laura Russell, Genevieve Arsenault-lapierre, Małgorzata J.m. Nowaczyk, Forbes D. Porter, Robert D. Steiner, Gustavo TureckiAbstract:OBJECTIVE: The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz Syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis. METHOD: Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz Syndrome and 54 matched comparison subjects. RESULTS: There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz Syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz Syndrome carriers than among the comparison subjects. CONCLUSIONS: These results, based on a unique study design, provide add...
Richard I. Kelley - One of the best experts on this subject based on the ideXlab platform.
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Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz Syndrome
Journal of medical genetics, 2004Co-Authors: Martina Witsch-baumgartner, Richard I. Kelley, M Gruber, H. G. Kraft, Massimiliano Rossi, Peter E. Clayton, M Giros, Dorothea Haas, M Krajewska-walasek, Gerd UtermannAbstract:BACKGROUND: Smith-Lemli-Opitz Syndrome (MIM 270400) is an autosomal recessive malformation and mental retardation Syndrome that ranges in clinical severity from minimal dysmorphism and mild mental retardation to severe congenital anomalies and intrauterine death. Smith-Lemli-Opitz Syndrome is caused by mutations in the Delta7 sterol-reductase gene (DHCR7; EC 1.3.1.21), which impair endogenous cholesterol biosynthesis and make the growing embryo dependent on exogenous (maternal) sources of cholesterol. We have investigated whether apolipoprotein E, a major component of the cholesterol transport system in human beings, is a modifier of the clinical severity of Smith-Lemli-Opitz Syndrome. METHOD: Common apo E, DHCR7, and LDLR genotypes were determined in 137 biochemically characterised patients with Smith-Lemli-Opitz Syndrome and 59 of their parents. RESULTS: There was a significant correlation between patients' clinical severity scores and maternal apo E genotypes (p = 0.028) but not between severity scores and patients' or paternal apo E genotypes. In line with their effects on serum cholesterol levels, the maternal apo epsilon2 genotypes were associated with a severe Smith-Lemli-Opitz Syndrome phenotype, whereas apo E genotypes without the epsilon2 allele were associated with a milder phenotype. The correlation of maternal apo E genotype with disease severity persisted after stratification for DHCR7 genotype. There was no association of Smith-Lemli-Opitz Syndrome severity with LDLR gene variation. CONCLUSIONS: These results suggest that the efficiency of cholesterol transport from the mother to the embryo is affected by the maternal apo E genotype and extend the role of apo E and its disease associations to modulation of embryonic development and malformations.
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The Smith-Lemli-Opitz Syndrome
Journal of medical genetics, 2000Co-Authors: Richard I. Kelley, Raoul C.m. HennekamAbstract:The Smith-Lemli-Opitz Syndrome (SLOS) is one of the archetypical multiple congenital malformation Syndromes. The recent discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism have led to important new treatment possibilities for affected patients. Moreover, the recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its effects on the expression of homeobox genes, has provided an explanation for the abnormal morphogenesis in the Syndrome. The well known role of cholesterol in the formation of steroid hormones has also provided a possible explanation for the abnormal behavioural characteristics of SLOS.
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Behavioral phenotype of RSH/Smith-Lemli-Opitz Syndrome.
Mental retardation and developmental disabilities research reviews, 2000Co-Authors: Elaine Tierney, Ngozi A. Nwokoro, Richard I. KelleyAbstract:Smith-Lemli-Opitz Syndrome (SLOS, RSH/SLO Syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation Syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz Syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz Syndrome is a metabolic disorder that is associated with autism. MRDD Research Reviews 2000;6:131-134.
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behavioral phenotype of rsh smith lemli Opitz Syndrome
Mental Retardation and Developmental Disabilities Research Reviews, 2000Co-Authors: Elaine Tierney, Ngozi A. Nwokoro, Richard I. KelleyAbstract:Smith-Lemli-Opitz Syndrome (SLOS, RSH/SLO Syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation Syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz Syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz Syndrome is a metabolic disorder that is associated with autism. MRDD Research Reviews 2000;6:131-134.