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Use of Cholic Acid in Smith-Lemli-Opitz Syndrome (SLOS): Real-World Patient Outcomes 

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in the DHCR7 gene, which encodes the enzyme 7-dehydrocholesterol reductase. SLOS is a multisystemic disorder affecting various aspects of a patient’s health and development including growth, development and behavior, and quality of life. This underscores the need for safe and efficacious interventions in attempts to limit disease burden. Deficiency in the DHCR7 enzyme leads to a “metabolic block” that results in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol (7-DHC) and the secondary isomer 8-dehydrocholesterol (8-DHC). Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol, which is coessential for the absorption of important nutrients. Bile acid supplementation with CA has been shown to improve dietary cholesterol absorption and raise plasma cholesterol levels. However, there is a paucity of patient level data regarding the utility of CA as a treatment for SLOS. The purpose of this case series is to address the lack of comprehensive patient data through documentation of the outcomes of a company sponsored CA patient experience program.

 

Methods:
A retrospective chart review was conducted in individuals with SLOS who received CA for at least 30 days through a company sponsored CA patient experience program. A standardized data collection tool was used by treating physicians to capture key clinical parameters including demographics, past medical history, current medications, key laboratory parameters, anthropomorphic, and behavioral data prior to starting CA through the most recent clinical follow up.

Results:
Eight genetically confirmed individuals with SLOS (50% male; 75% White; age range 12 months-20 years) with median plasma cholesterol at baseline ≤125 mg/dL were treated with CA at 10 mg/kg/day for two months to fifteen months in duration. Exogenous CA administration improved cholesterol levels in all eight patients signaling enhanced cholesterol metabolism in these patients. Growth metrics (eg, height and weight) improved after cholic acid initiation and trended toward age-appropriate growth percentiles. Caregiver reports, highlighting information from the patient, parent, and healthcare professional, recorded positive behavioral changes and improvements leading to increased social interaction, cognitive engagement, and improved communication skills after CA administration. Improvements in biochemical parameters along with improvements in quality of life were also observed in several patients after CA treatment. Cholic acid supplementation was well-tolerated in these patients with minimal adverse events. In this case series report, there was one patient who had "transient" color change in their fingers and toes that was considered treatment related.  

Conclusion:
The cumulative experiences of these eight patients provides a compelling narrative supporting the potential utility of CA treatment in SLOS while underscoring the safety of CA in this patient population. Larger, longitudinal studies of CA in SLOS are warranted.

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