Altered Cerebrospinal Fluid Proteins in Smith–Lemli–Opitz Syndrome

Smith–Lemli–Opitz Syndrome (SLOS) is a
rare, autosomal
recessive, neurocognitive disorder caused by pathological variants
in the 7-dehydrocholesterol reductase gene (DHCR7), leading to impaired cholesterol biosynthesis. The biochemical
results of these defects include the accumulation of the cholesterol
precursor, 7-dehydrocholesterol (7-DHC), and typically reduced cholesterol.
Individuals with SLOS present with a spectrum of developmental anomalies
and neurocognitive impairments. Despite various therapeutic approaches
being explored, there is no curative treatment, highlighting the need
for reliable biomarkers to better understand the disease’s
pathophysiology, allowing for important therapeutic intervention studies.
Here, we utilized discovery-based mass spectrometry to perform quantitative
proteomic profiling of cerebrospinal fluid (CSF) from SLOS individuals
compared to unaffected controls. Our analyses identified several differentially
expressed proteins that could serve as potential biomarkers for assessing
therapeutic efficacy and advancing our understanding of SLOS. Notably,
we observed previously unrecognized alterations in the reelin signaling
pathway and a decrease in dopamine excretion, implicating these processes
in the development and progression of the SLOS.