desmosterolosis

Desmosterolosis is a very rare sterol biosynthesis disorder that primarily affects multiple organ systems, particularly the central nervous system and skeletal structure. It is caused by pathogenic variants in the DHCR24 gene, which disrupts cholesterol metabolism and leads to elevated levels of desmosterol. Affected individuals typically present in early childhood with global developmental delay, spasticity, and structural brain anomalies. Given its extremely low occurrence, desmosterolosis affects fewer than 1 in a million people.

The clinical presentation of desmosterolosis is marked by a distinct set of features that are largely present in every affected individual. Key neurologic findings include global developmental delay and intellectual challenges, while brain imaging often reveals aplasia or hypoplasia and agenesis of the corpus callosum along with reduced cerebral white matter volume. Musculoskeletal and craniofacial features such as short stature, spasticity, micrognathia, and various dysmorphic ear configurations are also commonly observed. Other features like failure to thrive, abnormal cholesterol levels, and distal arthrogryposis occur in a significant number of cases. Not all individuals experience every feature, and severity varies considerably.

Desmosterolosis is caused by pathogenic variants in the DHCR24 gene, which plays a crucial role in cholesterol biosynthesis. Disruption of the normal function of this gene leads to abnormal accumulation of desmosterol and interferes with key developmental processes, particularly in the brain and skeletal tissues. The condition is inherited in an autosomal recessive pattern, meaning that affected individuals inherit two copies of the altered gene, one from each parent. This condition is more common when parents share a common ancestor, and genetic counseling is recommended to help families understand the implications and options for family planning.

Currently, management of desmosterolosis focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for this condition. Treatment typically involves a multidisciplinary team that may include neurologists, developmental specialists, and other healthcare providers who work together to address the multiple organ systems involved. In addition to managing active symptoms, regular surveillance is an essential part of long-term care, helping to identify potential complications early. Genetic counseling is recommended to provide guidance on treatment options and family planning considerations.

The course of desmosterolosis is highly variable, with outcomes depending on the severity of the clinical features and access to specialized care. Many affected individuals experience significant challenges early in life, but modern multidisciplinary management and ongoing surveillance can support improvements in quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families are encouraged to consult with specialists familiar with the condition, including genetic counselors, to gain a deeper understanding of potential long-term care strategies.

Clinical trials are underway exploring new treatment approaches for desmosterolosis. Individuals interested in learning more about emerging therapies are encouraged to search ClinicalTrials.gov or consult their care team about eligibility for available studies.