Smith-Lemli-Opitz syndrome

Last reviewed 04/2022

Described by Smith in 1964, this syndrome includes microcephaly, growth and mental retardation, unusual facial appearance, syndactyly of toes 2 and 3, and genital abnormalities. Multiple major structural abnormalities are the exception in SLOS patients surviving infancy.

Facial anomalies include ptosis, micrognathia and anteverted nares.

Genital abnormalities occur in males, and include hypospadias, cleft scrotum and cryptorchidism.

Developmental defects are generally associated with severe learning disability, although mild learning disability has been reported.

• an autosomal recessive human disease caused by mutations in the DHCR7 gene - which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7, EC1.3.1.21), the last enzyme in the cholesterol biosynthetic pathway
  • blocking cholesterol biosynthesis at that step leads to abnormal steady-state accumulation of dehydrosterols
    • particularly 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC), and reduced levels of cholesterol in all bodily tissues and fluids
    • 7DHC is highly reactive, giving rise to biologically active oxysterols
  • disease severity ranges from in utero or early postnatal death to mild symptoms
    • survivors typically exhibit a range of phenotypic abnormalities (dysmorphologies), as well as moderate to severe neurological, neurosensory and cognitive defects and diminished lifespan

Management

• current standard-of-care is dietary cholesterol supplementation
  • provides the missing or diminished end-product of the pathway (cholesterol), but it also should provide feed-back inhibition of the de novo pathway, thereby inhibiting further production and aberrant accumulation of cholesterol precursors
    • the treatment has variable, and typically minimal to modest, clinical efficacy (1)
      • use of statins (e.g., simvastatin), either alone or in combination with cholesterol supplementation also has been evaluated, with the rationale that a statin will block the de novo formation and accumulation of aberrant dehydrosterols, while exogenous cholesterol would, again, provide the missing requisite end-product of the pathway
• antioxidant treatment may be of benefit in this condition

Reference:

• Svoboda MD, Christie JM, Eroglu Y, Freeman KA, Steiner RD. Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders. Am J Med Genet C Semin Med Genet. 2012;160C:285-294
• Fliesler SJ. Antioxidants: The Missing Key to Improved Therapeutic Intervention in Smith-Lemli-Opitz Syndrome? Hereditary Genet. 2013 Dec 1;2(2):119.