Smith-Lemli-Opitz Syndrome: Cholesterol Metabolism Disorder and Neurodevelopmental Symptoms

Prof. Dr. Burak Tatlı
|
Saturday, September 17, 2022

Smith-Lemli-Opitz Syndrome: Comprehensive Guide

Overview

Smith-Lemli-Opitz Syndrome (SLOS) is a cholesterol metabolism disorder caused by deficiency of 7-dehydrocholesterol (7-DHC) reductase (DHCR7) enzyme.

Inheritance

It is inherited autosomal recessively.

Basic Symptoms

Microcephaly
Postaxial polydactyly
2-3 syndactyly in toes
Cognitive retardation

Diagnosis and Genetics

Diagnostic Test

Elevated 7-DHC level and DHCR7 gene mutation analysis (sequence and deletion/duplication analysis). Serum cholesterol concentration is usually low (not recommended for screening and diagnosis as it may be in normal range in approximately 10% of cases).

Genetic Counseling

It occurs due to homozygous or compound heterozygous pathogenic mutations in the DHCR7 gene. Frequency is increased in consanguineous marriages or marriages within the same settlement unit. The recurrence risk of the disease is 25%.

Frequency

SLOS incidence based on clinical features has been estimated as 1:20,000 to 1:60,000. Based on carrier frequency estimates, a higher incidence between 1:1,590-13,000 has been predicted.

Pathophysiology

Role of Cholesterol

Cholesterol has multiple biological functions. It is particularly necessary for the maturation of proteins in the “sonic hedgehog (SHH)” pathway, which is a fundamental regulator in growth-development and embryonic development of brain, face and midline.

Affected Systems

Neuroactive steroids
Bile acids
Steroid hormones
Neurosteroids
Oxysterols

Serotonin System

Excessive 7-DHC causes oxidative stress in tissues. As a result, the serotonergic system is affected during brain development. Increased expression of serotonin transporter proteins and increased serotonin in terminal synapses have been thought to be associated with autism spectrum disorder and abnormal behavioral phenotype in SLOS patients.

Genetic Mutations

More than 200 different DHCR7 mutations have been reported in SLOS cases so far. The most commonly reported mutation is c.964-1G>C mutation that causes splicing error, reported in one-third of SLOS cases.

Common Mutations

p.T93M (10%)
p.W151X (6%)
p.R404C (5%)
p.V326L (5%)
R352W (<5%)

Phenotypic Features

Typical Presentation

Cases with microcephaly with polydactyly and 2-3 syndactyly of toes accompanied by prominent and characteristic facial features, having autism and/or cognitive retardation is the typical presentation of SLOS syndrome.