Identification of three patients with a very mild form of Smith‐Lemli‐Opitz syndrome

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Abstract
Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by mental retardation, congenital anomalies, and growth deficiency. The syndrome is caused by a block in cholesterol biosynthesis at the level of 7‐dehydrocholesterol reductase (7‐DHCR), which results in elevated levels of the cholesterol precursor 7‐dehydrocholesterol (7‐DHC) and its isomer 8‐dehydrocholesterol (8‐DHC). We report on three patients from two families with a very mild clinical presentation of SLOS. Their plasma cholesterol values were normal and their plasma levels of 7‐ and 8‐ DHC were only slightly elevated. In cultured skin fibroblasts, a significant residual 7‐DHCR activity was found. All three patients were compound heterozygotes for a novel mutation affecting translation initiation (M1L). Two of them had the common IVS8‐1G>C null mutation and the third patient an E448K mutation in the 7‐DHCR gene. Our findings emphasize the importance of using a sensitive method for measuring precursors of cholesterol in combination with mutation analysis to analyze patients with only minimal clinical SLOS‐like signs.

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