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Assessment of whole body cholesterol pool size in Smith‐Lemli‐ Opitz syndrome children using liquid chromatography tandem mass spectrometry

Smith‐Lemli‐Opitz syndrome (SLOS) patients typically exhibit abnormally low cholesterol, high 7‐dehyrocholesterol (DHC) and 8‐DHC levels in tissues and plasma. Therapeutic intervention for SLOS is aimed at maximizing whole body cholesterol pool size (WBCP) while down‐regulating biosynthesis to decrease the buildup of potentially toxic precursors. The study aim was to develop a sensitive liquid chromatography‐tandem mass spectrometry (LC/MS/MS) method for detection of changes in blood isotope cholesterol enrichment over time, for assessment of WBCP in SLOS patients receiving supplemental dietary cholesterol. Subjects (n=13; mean age: 7±1 yr) were given iv [18O]cholesterol (1.0–1.4 mg/kg bodyweight) or D7‐cholesterol (0.9–1.4 mg/kg). Blood samples were collected at baseline and over a 10 wk period, cholesterol extracted from RBC, derivatized with piconyl ester and analyzed using LC/MS/MS. The [M+H] +>[M‐picolinic acid] + transition was chosen for monitoring, with 18O‐cholesterol at m/z 494>369 and D7‐cholesterol at 499>376. WBCP was 427.3 ±52.0 mg/kg bodyweight. Plasma cholesterol level was not related to WBCP (p>0.05), but inversely related to 7DHC and 8DHC (p<0.05). In summary, LC/MS/MS is a sensitive method for stable isotopic assessment of WBCP in humans. This study is the first assessment of WBCP in children and in SLOS patients. The data will be a useful reference for a longitudinal SLOS study.