Symposium on porphyrins: Part IIA newly recognized syndromeof multiple congenital anomalies**
Three unrelated male children have been found to have a strikingly similar pattern ofmultiple congenital anomalies which suggests a common etiology. In addition to relative microcephaly with mental retardation and hypertonicity, these patients have incomplete development of the external genitals and abnormalities of the face, hands, and feet. Congenital pyloric stenosis was present in two of them. No chromosomal abnormality was found and the cause remains obscure though the apparent occurrence of the same condition in a deceased sibling of one of the patients suggests a genetic determination.
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Cholesterol metabolism pathway in autism spectrum disorder: From animal models to clinical observations
2023, Pharmacology Biochemistry and BehaviorAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a persistent impairment of social skills, including aspects of perception, interpretation, and response, combined with restricted and repetitive behavior. ASD is a complex and multifactorial condition, and its etiology could be attributed to genetic and environmental factors. Despite numerous clinical and experimental studies, no etiological factor, biomarker, and specific model of transmission have been consistently associated with ASD. However, an imbalance in cholesterol levels has been observed in many patients, more specifically, a condition of hypocholesterolemia, which seems to be shared between ASD and ASD-related genetic syndromes such as fragile X syndrome (FXS), Rett syndrome (RS), and Smith- Lemli-Opitz (SLO). Furthermore, it is known that alterations in cholesterol levels lead to neuroinflammation, oxidative stress, impaired myelination and synaptogenesis. Thus, the aim of this review is to discuss the cholesterol metabolic pathways in the ASD context, as well as in genetic syndromes related to ASD, through clinical observations and animal models. In fact, SLO, FXS, and RS patients display early behavioral markers of ASD followed by cholesterol disturbances. Several studies have demonstrated the role of cholesterol in psychiatric conditions and how its levels modulate brain neurodevelopment. This review suggests an important relationship between ASD pathology and cholesterol metabolism impairment; thus, some strategies could be raised – at clinical and pre-clinical levels – to explore whether cholesterol metabolism disturbance has a generally adverse effect in exacerbating the symptoms of ASD patients.
Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-Lemli-Opitz Syndrome
2023, Avery's Diseases of the NewbornThis chapter covers a broad range of genetic disorders that can present in the newborn period including peroxisomal disorders, congenital disorders of glycosylation, and Smith-Lemli-Opitz syndrome. The chapter focuses on the clinical presentations in the neonate and infant, diagnostic methods, and treatment options for these disorders. The phenotypic presentation of congenital disorders of glycosylation is broad ranging from mild to severe and from single organ system to multisystem involvement. Congenital disorders of glycosylation should be considered in any unexplained clinical condition, but especially in multisystemic, neurologic conditions. Most diagnoses occur via molecular testing. Treatment is largely supportive with rare exceptions where nutritional supplements have improved symptoms. Peroxisomal disorders are a heterogeneous group of disorders resulting from the absence or dysfunction of one or more peroxisomal enzymes. Features are varied, but include craniofacial dysmorphism, neurologic dysfunction, hepato-digestive dysfunction, renal cysts, and skeletal abnormalities. Diagnosis is best made by next-generation sequencing following screening biochemical tests. Treatment is largely symptomatic and supportive except for hematopoietic stem cell transplant in the cerebral form of X-linked adrenoleukodystrophy that is included in the newborn screen in many states. Smith-Lemli-Opitz (SLO) syndrome is a multisystemic, developmental, and dysmorphic syndrome caused by a defect in cholesterol biosynthesis. Diagnosis is based on finding elevated 7-dehydrocholesterol and 8-dehydrocholoesterol levels in the blood. Treatment involves cholesterol supplementation with supportive care.
Measurement of 7-dehydrocholesterol and cholesterol in hair can be used in the diagnosis of Smith-Lemli-Opitz syndrome
2022, Journal of Lipid Research7-dehydrocholesterol (7-DHC) and cholesterol (CHOL) are biomarkers of Smith-Lemli-Opitz Syndrome (SLOS), a congenital autosomal recessive disorder characterized by elevated 7-DHC level in patients. Hair samples have been shown to have great diagnostic and research value, which has long been neglected in the SLOS field. In this study, we sought to investigate the feasibility of using hair for SLOS diagnosis. In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), hair samples were completely pulverized and extracted by micro-pulverized extraction in alkaline solution or in n-hexane. After microwave-assisted derivatization with N,O-Bis(trimethylsilyl)trifluoroacetamide, the analytes were measured by GC-MS. We found that the limits of determination for 7-DHC and CHOL were 10 ng/mg and 8 ng/mg, respectively. In addition, good linearity was obtained in the range of 50–4000 ng/mg and 30–6000 ng/mg for 7-DHC and CHOL, respectively, which fully meets the requirement for SLOS diagnosis and related research. Finally, by applying the proposed method to real hair samples collected from 14 healthy infants and two suspected SLOS patients, we confirmed the feasibility of hair analysis as a diagnostic tool for SLOS. In conclusion, we present an optimized and validated analytical method for the simultaneous determination of two SLOS biomarkers using human hair.
Rare monogenic disorders of cholesterol metabolism
2022, Cholesterol: From Chemistry and Biophysics to the ClinicAlmost all monogenic diseases of cholesterol metabolism are classified as rare (less than 1 in 2000 people) or ultra-rare with the exception of heterozygous familial hypercholesterolemia, which is a relatively common genetic disorder (1 in 250 individuals). These disorders are caused by numerous rare mutations in genes related to lipid metabolism. Although each rare disease affects a small number of people, together these diseases constitute a significant burden to the health of the population.
In this chapter, we review the main categories of inherited rare and ultra-rare disorders related with cholesterol metabolism. The diseases were grouped into four main sections based on changes in lipid profile, namely hypercholesterolemia, sterol storage diseases, inborn errors of bile acid synthesis, and hypocholesterolemia.
Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis
2021, Cell ReportsClathrin-mediated endocytosis (CME) is critical for cellular signal transduction, receptor recycling, and membrane homeostasis in mammalian cells. Acute depletion of cholesterol disrupts CME, motivating analysis of CME dynamics in the context of human disorders of cholesterol metabolism. We report that inhibition of post-squalene cholesterol biosynthesis impairs CME. Imaging of membrane bending dynamics and the CME pit ultrastructure reveals prolonged clathrin pit lifetimes and shallow clathrin-coated structures, suggesting progressive impairment of curvature generation correlates with diminishing sterol abundance. Sterol structural requirements for efficient CME include 3′ polar head group and B-ring conformation, resembling the sterol structural prerequisites for tight lipid packing and polarity. Furthermore, Smith-Lemli-Opitz fibroblasts with low cholesterol abundance exhibit deficits in CME-mediated transferrin internalization. We conclude that sterols lower the energetic costs of membrane bending during pit formation and vesicular scission during CME and suggest that reduced CME activity may contribute to cellular phenotypes observed within disorders of cholesterol metabolism.
Voltammetry of 7-dehydrocholesterol as a new and useful tool for Smith-Lemli-Opitz syndrome diagnosis
2021, Talanta7-Dehydrocholesterol is an essential biomarker of Smith-Lemli-Opitz syndrome, a congenital autosomal recessive disorder. This study shows for the first time that electrochemical oxidation of 7-dehydrocholesterol can be used for its voltammetric determination. Two classes of supporting electrolytes in acetonitrile and a mixture of acetonitrile-water were used: inorganic acids known to promote structural changes of steroids and indifferent electrolytes. Oxidation of 7-dehydrocholesterol at ca +0.8 V (vs. Ag/AgNO3 in acetonitrile) in 0.1 mol L−1 NaClO4 in acetonitrile is useful for its voltammetric detection using common bare electrode materials. Detection limits for 7-dehydrocholesterol lie in the low micromolar range for all the working electrodes, including boron-doped diamond (0.4 μmol L−1) and disposable thin-film platinum electrodes (0.5 μmol L−1), which are advantageous because of the low volumes of studied solutions. After Bligh-Dyer extraction, quantification of 7-dehydrocholesterol concentration (boron-doped diamond) or concentration range (thin-film platinum) is easily attainable in artificial serum. The mere knowledge of the concentration range provides clinically valuable information, as 7-dehydrocholesterol levels are employed for SLOS diagnosis as a binary criterion (elevated, tens to hundreds μmol L−1 in symptomatic/non-elevated, typically bellow 1 μmol L−1 in healthy individuals in plasma). Moreover, it is shown that 7-dehydrocholesterol (provitamin D3) and cholecalciferol (vitamin D3) can be oxidized in 0.1 mol L−1 HClO4 in acetonitrile. Under these conditions, their voltammetric response changes dramatically, and their oxidation potential difference transiently increases from 0.08 V to 0.25 V, which should facilitate their simultaneous voltammetric determination. This work constitutes a foundation for a reliable and straightforward method for Smith-Lemli-Opitz syndrome diagnosis and monitoring 7-dehydrocholesterol’s biotransformation to cholecalciferol.
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This work was supported by a grant from the National Foundation, by a Public Health Service Research Career Program Award No. GH-K3-14,022 from the General Medicine Institute (D.W.S.), and by a Public Health Service Fellowship Grant GPD-18,982 (J.M.O.).
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Associate Professor of Pediatrics, Universityof Wisconsin, University Hospitals, 1300 University Avenue, Madison 6, Wis.