Altered cerebrospinal fluid proteins in Smith–Lemli–Opitz syndrome patients

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation syndrome with neurocognitive impairment. SLOS arises from mutations in the 7-dehydrocholesterol reductase gene which results in impaired enzymatic conversion of 7-dehydrocholesterol to cholesterol. In the current work, we sought to measure proteins that were altered in the cerebrospinal fluid from SLOS patients compared to pediatric controls. Using a multi-analyte antibody-based assay, we found that 12 proteins are altered in SLOS patients. Validation studies were carried out and the findings from this study suggest alterations in extracellular matrix remodeling and further evidence of oxidative stress within the disease pathophysiology. The results of this study will be used to explore biological pathways altered in SLOS and identifies a set of cerebral spinal fluid proteins that can be evaluated as biomarkers in future therapeutic trials.

Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin-mediated endocytosis

“…Endocytic deficits could contribute to feeding difficulties and gastrointestinal intolerance observed in SLOS. Reduced TfR-mediated internalization may explain the observed increased levels of Tfn protein present within the retina of AY9944-treated rats (Tu et al, 2013) and cerebrospinal fluid of SLOS subjects (Cologna et al, 2016). Cholesterol's complex role in different cellular functions indicates that malformations and functional deficits observed within disorders of cholesterol synthesis could be due to competing and disparate effects of the lipid.…”

Sterols lower energetic barriers of membrane bending and fission necessary for efficient clathrin mediated endocytosis

“…As such, endocytic deficits could contribute to feeding difficulties and gastrointestinal intolerance commonly observed in SLOS. Previous studies have also observed increased levels of Tfn protein present within the retina of AY9944-treated rats (Tu et al, 2013) and cerebrospinal fluid isolated from SLOS subjects (Cologna et al, 2016), possibly due to reduced TfR-mediated internalization. The varied and complex role of cholesterol in different cellular functions indicates that malformations and functional deficits observed within disorders of cholesterol synthesis could be due to competing and disparate effects of the lipid.…”