Squalene Synthase Deficiency

Clinical characteristics: Squalene synthase deficiency (SQSD) is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to Smith-Lemli-Optiz syndrome. Key clinical features include facial dysmorphism, a generalized seizure disorder presenting in the neonatal period, nonspecific structural brain malformations, cortical visual impairment, optic nerve hypoplasia, profound developmental delay / intellectual disability, dry skin with photosensitivity, and genital malformations in males.

Diagnosis/testing: Individuals with SQSD have a unique urine metabolic profile with increased saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol. The diagnosis of squalene synthase deficiency is established in a proband with characteristic urine metabolites on urine organic acids analysis or by the identification of biallelic pathogenic variants in FDFT1 by molecular genetic testing.

Management: Treatment of manifestations: Currently there are no specific disease-modifying treatments. Standard treatment for epilepsy, congenital heart defects, constipation, cryptorchidism, hypospadias, spasticity, and developmental delay / intellectual disability is appropriate. Feeding therapy may be useful, although placement of a gastrostomy tube is recommended for those with dysphagia and/or poor growth. In those with visual impairment, early intervention may help to stimulate visual development. In those with sleep disturbance, a trial of melatonin may be considered.

Surveillance: At each visit: assess for new manifestations such as seizures, changes in tone, and movement disorder; monitor developmental progress, educational needs, and behavior; assess for evidence of aspiration or respiratory insufficiency; assess for evidence of sleep disorder; monitor growth, nutritional status, and signs and symptoms of constipation. Ophthalmology evaluation annually or as clinically indicated.

Agents/circumstances to avoid: Sun and UV light exposure; skin photosensitivity has produced clinically significant UV-related sunburns within ten minutes of direct sunlight exposure.

Genetic counseling: SQSD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% change of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the FDFT1 pathogenic variants in the family are known.