RESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder caused by pathological variants in DHCR7, resulting in a deficiency in the enzyme 7-dehydrocholesterol reductase. This results in elevated levels of cholesterol precursors and typically low cholesterol levels, leading to a range of physical and cognitive challenges. Mortality rates in infants with severe SLOS are high, due to congenital malformations. Premature death has been described in individuals with SLOS, particularly in severely affected individuals. Further research is needed to understand postnatal mortality risk factors for individuals with SLOS. Understanding these factors could improve monitoring and prevention efforts. To investigate this, we obtained death certificates from the National Death Index (NDI) database on a cohort of individuals with SLOS who were enrolled in natural history studies at the National Institutes of Health Clinical Center (NCT00001721 and NCT05047354). Analysis and comparison of this deceased cohort showed that although premature death occurs in SLOS, many individuals with SLOS survive into adulthood. We also observed the risk of postnatal mortality increasing with higher severity scores and lower initial cholesterol levels. Trial Registration: NCT00001721 and NCT05047354.
RESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.