Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomaly (MCA)/intellectual disability (ID) syndrome caused by a defect in cholesterol synthesis.
An autosomal recessive genetic condition, it results from a deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase (7-dehydrocholesterol-delta 7-reductase [DHCR7] EC 188.8.131.52), the final enzyme in the sterol synthetic pathway that converts 7-dehydrocholesterol (7DHC) to cholesterol. Smith-Lemli-Opitz syndrome is usually suspected clinically, but the diagnosis must be confirmed by biochemical and/or molecular genetic studies. Currently, no treatment has proven effective long-term for patients with the syndrome.
Affected individuals usually have low plasma cholesterol levels and invariably have elevated levels of cholesterol precursors, including 7DHC. The most severely affected individuals (those with the condition formerly referred to as Smith-Lemli-Opitz syndrome type II) have multiple congenital malformations and are often miscarried or stillborn or die in the first weeks of life. Dysmorphic facial features, microcephaly, second-toe and third-toe syndactyly, other malformations, and intellectual disability (ID) are typical. Mildly affected individuals may have only subtle dysmorphic features and, often, learning and behavioral disabilities.
See the image below.
Child with Smith-Lemli-Opitz syndrome.
Signs and symptoms
The following signs and symptoms may be noted in Smith-Lemli-Opitz syndrome:
Obtundation or coma
Failure to thrive
Congestive heart failure
Neuropsychiatric and neurodevelopmental abnormalities are common and include variable intellectual disability (ID), aberrant behavior, and autism.
Fetal ultrasonography may reveal anomalies suggestive of Smith-Lemli-Opitz syndrome. Confirmatory prenatal diagnostic testing is currently available by genetic mutation analysis.
Postnatally, the syndrome is usually suspected clinically, but biochemical and/or genetic testing is necessary for diagnosis. Plasma total cholesterol and/or low-density lipoprotein (LDL) cholesterol levels may be low but are not universally low. Measurement of plasma sterols, including, at a minimum, cholesterol and 7DHC, is the biochemical test for Smith-Lemli-Opitz syndrome.
As mentioned, no treatment has so far proven effective long-term for patients with Smith-Lemli-Opitz syndrome.
Potentially, cholesterol supplementation is a logical treatment because it may be expected to raise plasma and tissue cholesterol levels. By feedback inhibition of hydroxymethylglutaryl-coenzyme-A-reductase, cholesterol supplementation may reduce levels of 7DHC and related cholesterol intermediates that may be toxic. Some suggestion of a potential therapeutic response has been seen with hydroxymethylglutaryl-coenzyme-A-reductase inhibitors (statins), but adverse events are not infrequent.