Use of cholic acid in Smith-Lemli-Opitz syndrome (SLOS): real-world patient outcomes.

Abstract

Background: Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a "metabolic block" resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and essential for cholesterol absorption. Dietary cholesterol supplementation is standard therapy. 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. A retrospective chart review was conducted for these individuals while on CA plus cholesterol supplementation. Data for demographics and key clinical/laboratory parameters were captured with a standardized data collection tool.

Results: Eight genetically confirmed individuals with SLOS (age range 1 to 20 years) with median plasma cholesterol levels at baseline ≤ 125 mg/dL were treated with CA at 10-15 mg/kg/d for 30 to 450 days. Exogenous CA administration improved cholesterol levels in the majority of patients. Growth improved after CA initiation and trended toward age-appropriate growth percentiles. Reports from the patient, parent/caregiver, and/or healthcare professional noted positive behavioral changes leading to increased social interaction, cognitive engagement, and improved communication skills. Improvements in biochemical parameters and quality of life were also observed in several patients after CA treatment. CA supplementation was well tolerated with minimal adverse events.

Conclusions: The cumulative experiences of eight patients provide 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 patients with SLOS are warranted.