Abstract
Only four of over 30 possible defects of cholesterol biosynthesis have been described. Mevalonic aciduria due to mevalonate kinase deficiency is situated at the beginning of the pathway and compromises the production of nonsterol isoprenes in addition to cholesterol. Patients with this enzyme defect show a wide range of symptoms, particularly dysmorphic features, hypotonia, developmental delay, enteropathy, hepatosplenomegaly, and recurrent febrile crises. At the end of the pathway, a defect of 3β- hydroxysterol-∆7-reductase could be delineated as the cause of Smith-Lemli-Opitz syndrome (SLOS), an important multiple malformation syndrome. Amongst these malformations are a characteristic facial appearance and syndactyly of toes 2–3. Deficiency of sterol-∆8-isomerase can cause a chondrodysplasia punctata phenotype ranging from mild Conradi-Hünermann to a lethal chondrodysplasia. One child with a malformation syndrome different from SLOS and generalized accumulation of desmosterol can be assumed to have suffered from a deficiency of 3β-hydroxysterol-∆24-reductase. Further defects are likely to be unraveled in due course and Table 29.1 summarizes indications for the two available tests: determination of mevalonic acid by urinary organic acid analysis and sterol analysis by gas chromatography-mass spectrometry (GCMS).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Hoffmann GF, Charpentier C, Mayatepek E et al. (1993) Clinical and biochemical phenotype in eleven patients with mevalonic aciduria. Pediatrics 91: 915–921
Hinson DD, Rogers ZR, Hoffmann GF et al. (1998) Hematological abnormalities and cholestatic liver disease in two patients with mevalonate kinase deficiency. Am J Med Gen 78: 408–412
Hoffmann GF, Wiesmann UN, Brendel S, Keller RK, Gibson KM (1997) Regulatory adaptation of isoprenoid biosynthesis and the LDL-receptor pathway in fibroblasts from patients with mevalonate kinase deficiency. Pediatr Res 41: 541–546
Hübner C, Hoffmann GF, Charpentier C et al. (1993) Decreased plasma ubiquinon-io concentration in patients with mevalonic aciduria. Pediatr Res 34129–133
Hoffmann GF, Hunneman DH, Sweetman L et al. (1991) Facts and artefacts in mevalonic aciduria: development of a stable isotope dilution GCMS assay for mevalonic acid and its application to physiological fluids, tissue samples, prenatal diagnosis and carrier detection. Clin Chim Acta 198: 209228
Gibson KM, Hoffmann GF, Tanaka RD, Bishop RW, Cham-bliss KL (1997) Mevalonate kinase map position 12q24. Chromos Res 5: 150
Hinson DD, Shaw JL, Kozich V et al. (1999) Identification of four new mutations in mevalonate kinase deficiency, including one in a patient of mennonite ancestry. Am J Hum Genet 65: 327–335
Krisans S, Keller RK, Gibson KM (1997) Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem 42: 26756–26760
Smith DW, Lemli L, Opitz JM (1964) A newly recognized syndrome of multiple congenital anomalies. J Pediatr 64: 210–217
Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI (1997) Clinical and biochemical spectrum of patients with RSH/ Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 68: 263–269
Curry CJ, Carey JC, Holland JS et al. (1987) Smith-LemliOpitz syndrome type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 26: 45–57
Kelley RI (1996) Smith-Lemli-Opitz syndrome. In: Moser HW (ed) Neurodystrophies and neurolipidoses. Elsvier Science, Amsterdam (Handbook of clinical neurology, vol 22/66)
Tint GS, Irons M, Elias ER et al. (1994) Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 33oa07–113
Kelley RI (1995) Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and coltured skin fibroblasts. Clin Chim Acta 236: 45–58
Abuelo DN, Tint GS, Kelley R et al. (1995) Prenatal detection of the cholesterol biosynthetic defect in the Smith-LemliOpitz syndrome by the analysis of amniotic fluid sterols. Am J Med Genet 56: 281–285
Mills K, Mandel H, Montemagno R et al. (1996) First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency). Pediatr Res 39: 816–819
Elias ER, Irons MB, Hurley AD, Tint GS, Salen G (1997) Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome ( SLOS ). Am J Med Genet 68: 305–310
Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H (1998) Molecular cloning and expression of the human delta 7-sterol reductase. Proc Natl Acad Sci USA 95: 1899–1902
Fitzky BU, Witsch-Baumgartner M, Erdel M et al. (1998) Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci USA 95: 8181–8186
Waterham HR, Wijburg FA, Hennekam RCM et al. (1998) Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am J Hum Genet 63: 329–338
Wassiff CA, Maslen C, Kachilele-Linjewile S et al. (1998) Mutations in the human sterol 47-reductase gene at ng12–13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet 63: 55–62
Kelley RI, Wilcox WG, Smith M et al. (1999) Abnormal sterol metabolism in patients with Conradi-Hünermann-Haplle syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet 83: 213–219
FitzPatrick DR, Keeling JW, Evans MJ et al. (1998) Clinical phenotype of desmosterolosis. Am J Med Genet 75: 145–152
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Hoffmann, G.F., Haas, D. (2000). Disorders of Cholesterol Synthesis. In: Fernandes, J., Saudubray, JM., Van den Berghe, G. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04285-4_29
Download citation
DOI: https://doi.org/10.1007/978-3-662-04285-4_29
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-04287-8
Online ISBN: 978-3-662-04285-4
eBook Packages: Springer Book Archive