Genetic defects in enzymes responsible for cholesterol biosynthesis have emerged as important causes of congenital dysmorphology and retardation syndromes. Cholesterol is an important constituent of the cell membrane of most eukaryotic cells, in myelin formation in the brain, spinal cord, and peripheral nervous system, and acts as the precursor for steroid hormones and bile acids. Finally, cholesterol has important interactions with proteins, which control embryonic development. To date, eight distinct inherited disorders have been linked to different defects in cholesterol biosynthesis. Two result from an enzyme defect in the pre-squalene segment of the pathway: the classical form of mevalonic aciduria and the hyperimmunoglobulinemia D syndrome, also known as Dutch-type periodic fever. Six defects in the post-squalene segment of the pathway include: Smith-Lemli-Opitz syndrome, two X-linked dominant inherited and male-lethal disorders, Conradi-Hünermann-Happle syndrome and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD), and at least three extremely rare autosomal recessive disorders, Greenberg skeletal dysplasia, lathosterolosis, and desmosterolosis. All these inborn errors known to date have been linked to deficiency of specific enzymes on the basis of elevated levels of specific sterol intermediates in tissues of affected patients followed by demonstrating disease-causing mutations in the encoding genes. These cholesterol deficiency multiple malformation-retardation syndromes have clinical overlap. Besides psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, and cataract, impaired cholesterol biosynthesis is associated with autism and other behavioral disorders.
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