What is the pathophysiology of Smith-Lemli-Opitz syndrome (SLOS)?

Updated: Jan 27, 2021
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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The classic paradigm for the pathogenesis of an inborn error of metabolism includes the accumulation of a toxic precursor and/or deficiency of an essential product as a result of an enzyme deficiency. In the case of Smith-Lemli-Opitz syndrome, the precursor 7DHC is potentially toxic in high concentrations, and cholesterol deficiency is almost certainly detrimental.

Smith, Lemli, and Opitz initially described Smith-Lemli-Opitz syndrome (while working at the University of Wisconsin) as a genetic MCA/ID syndrome, in 1964. [3] They named the condition RSH after the first initial of the last names of the first 3 patients ascertained. [4] The clinical characteristics of Smith-Lemli-Opitz syndrome have been well established over the past 4 decades.

The etiology of Smith-Lemli-Opitz syndrome was unknown until 1993, when Irons et al discovered that patients with Smith-Lemli-Opitz syndrome had low plasma cholesterol levels and accumulated sterol precursors such as 7DHC. [5] A deficiency of the microsomal enzyme DHCR7, which reduces the 7-8 double bond of 7DHC to form cholesterol in the final step of the cholesterol synthetic pathway, was hypothesized and later proven to cause Smith-Lemli-Opitz syndrome. Mutations in the DHCR7 gene are responsible for Smith-Lemli-Opitz syndrome. Therefore, Smith-Lemli-Opitz syndrome can now be considered a classic inborn error of metabolism.

Currently, the reason defects in cholesterol synthesis cause congenital malformations is not known. Several disparate lines of research have led to recent understanding of the critical and somewhat unexpected role of cholesterol in early human development. Cholesterol is important in cell membranes, serves as the precursor for steroid hormones and bile acids, and is a major component in myelin. Cholesterol is covalently bound to the embryonic signaling protein sonic hedgehog (Shh) in a necessary step of the autoprocessing of the precursor to active form, occurring about gestational day 0-7 in humans.

Shh plays a critical role in several embryologic fields relevant to Smith-Lemli-Opitz syndrome (eg, brain, face, heart, limbs). Therefore, cholesterol is an essential triggering agent in the early developmental program of the human. Because 7DHC can also activate Shh, cholesterol deficiency that leads to decreased activation of Shh is probably not the sole explanation for congenital malformations in this syndrome.

Abnormalities in the Shh-patched signaling cascade presumably play a role. Membrane instability and dysmyelination from cholesterol deficiency and accumulation of 7DHC and other potentially toxic cholesterol precursors are also likely to contribute to the Smith-Lemli-Opitz syndrome phenotype.

Increased isoprenoids were reported in Smith-Lemli-Opitz syndrome, but the role these nonsterol isoprenoids play in the pathophysiology of this disorder is unclear. [6]

A study by Merkens et al indicated that high 7DHC plasma levels correlate with feeding difficulties in patients with Smith-Lemli-Opitz syndrome. In the report, which involved 26 patients (aged 0.4-19 years) with the syndrome, the investigators found that patients with a plasma level of more than 0.24 mmol/L or a cholesterol concentration of less than 1.95 mmol/L were more likely to require use of a gastrostomy tube. [7]

A study by Sparks et al found reduced levels of the neurotransmitter metabolites 5-hydroxyindoleacetic acid (from serotonin) and homovanillic acid (from dopamine) in the cerebrospinal fluid of patients with Smith-Lemli-Opitz syndrome. The investigators suggested that this may result from a sterol-associated defect in synaptic vesicle development. [8]

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