Smith-Lemli-Opitz Syndrome: From Biochemical Mechanisms to Clinical Implications

Clinical Manifestations of SLOS

Physical Anomalies

The physical features of SLOS patients are quite diverse, and the degree of implication of the given changes might differ as well. Some of the obvious characteristics are growth delays, microcephaly, a broad nasal bridge, a small chin, syndactyly, and polydactyly. Abnormalities to the genitalia may entail hypospadias in males and ambiguous genitalia in females.

Neurological and Behavioral Symptoms

As previously mentioned, neurological abnormalities are characteristic of SLOS. It is common to see patients with this disease with intellectual disability, developmental delay, and behavioral disorders. These can, for example, be hyperactivity, aggressiveness, and self-mutilation, as well as indications of autism. It is also evident that the extent of neurological involvement ranges from severe, where some of these patients have severe intellectual disability, to moderate, where some of these patients have moderate intellectual disability.

In SLOS patients, many studies using brain imaging show structural changes in the cerebral surface, such as in the corpus callosum, cerebral and cerebellar atrophy, midline defects, and so on. The mentioned structural changes can be associated with inadequate cholesterol metabolism influencing the development of the brain.

Metabolic and Endocrine Dysfunctions

Aside from neurological and physical changes, the metabolic effects due to disturbed cholesterol synthesis are numerous. Cholesterol is a precursor for the steroid hormone, and therefore, if cholesterol is in short supply, hormone synthesis will be affected. For example, some SLOS patients are diagnosed with adrenal insufficiency, which, of course, needs hormone replacement therapy.

Diagnostic Approaches

Biochemical Testing

The diagnosis of SLOS, like other L/km disorders, mainly relies on biochemical analysis, where blood samples of the patient are analyzed to detect the level of 7-DHC and cholesterol. High levels of 7 DHC and low levels of cholesterol are observed in the condition. Mass spectrometry is considered the best technique for the identification and measurement of such sterols.

Genetic Testing

Companion diagnosis is done through molecular tests to detect genetic changes in the DHCR7 gene. In total, 117 different mutations have been reported, and they are categorized by the effect that they have on the enzyme function of the protein. Apart from confirming the diagnosis, genetic testing also helps in counseling the affected families on the next course of action.

Therapeutic Interventions

Dietary Cholesterol Supplementation

Due to the lack of cholesterol, the diet has always been used to supplement SLOS treatment, though not as a major solution. The results of cholesterol supplementation have revealed increased growth, decreased biochemical imbalance, and positive changes in some children’s behavioral patterns. However, the effectiveness of this intervention is somewhat therapeutic and does not fully eliminate all the clinical manifestations of the disorder.

Antioxidant Therapy

Considering that 7-DHC undergoes a process of oxidation rather easily, antioxidant therapy has been proposed as a treatment for oxidative stress and its effects on the body. There are clinical trials in which antioxidants and vitamin E have been administered, and some decreases in oxidative markers have been observed.

Pharmacological Approaches

Effort continues to be made to determine other drugs that could affect the biosynthesis of cholesterol and decrease 7-DHC levels. One of them is statin, which is described as an HMG-CoA reductase inhibitor that is the key enzyme in the synthesis of cholesterol. Thus, by lowering the overall flux through the cholesterol pathway, statins could help to reduce the deposits of 7-DHC. Nevertheless, statins’ use to manage SLOS is still investigational, and additional studies are required to define their risks and benefits.

Future Directions and Research

Over the past decades, there have been improvements in the comprehensiveness of SLOS; however, there are still many questions left unanswered. Future research is still underway to describe the specific process through which 7-DHC and its oxysterols further contribute to the disease symptoms observed in SLOS. Also, to precisely consider the benefits and adverse effects of today’s promising therapeutic approaches, there is an urgency to carry out large-scale clinical trials.

There is hope that with future development in gene therapy, conditions such as SLOS can be managed. Thus, while gene therapy for SLOS is still only in the experimental phase, it holds the promise of actually curing the disease by rectifying the genetic mutation that leads to an impairment of cholesterol synthesis.

Conclusion

Smith-Lemli-Opitz Syndrome is a multifaceted disorder that impacts virtually all areas of growth and development. Much about the disease has been discovered about the biochemical processes that are involved, making diagnosis and treatment possible. However, additional research is needed to completely understand and describe the condition of SLOS and to enhance the opportunities of its therapy. With this increased understanding, there is hope for the condition to improve in the future and for patient’s well-being to be enhanced once they are diagnosed with this difficult disease.

References

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