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: asses 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.

Suggestive Findings

Squalene synthase deficiency should be suspected in individuals with clinical manifestations similar to Smith-Lemli-Optiz syndrome and the following clinical, laboratory, and brain MRI findings.

Clinical findings

• Dysmorphic features (See Clinical Description, Dysmorphic features.)
• Neonatal generalized seizure disorder
• Profound developmental delay
• Cortical visual impairment
• Genital malformations in males
• Dry skin with photosensitivity

Laboratory findings. Gas chromatograph - mass spectroscopy (GC-MS) and nuclear magnetic resonance spectroscopy (NMRS) of urine metabolites are listed in Table 1.

GC-MS = gas chromatograph - mass spectroscopy; NMRS = nuclear magnetic resonance spectroscopy

Note: A similar metabolite profile is also found in the urine of humans treated with pharmacologic inhibitors of squalene synthase or those who have taken farnesol [Jemal & Ouyang 1998, Coman et al 2018]:

• Increased plasma farnesol levels
• Plasma squalene levels that are either reduced or normal
• Fasting cholesterol studies demonstrating:
  • Low normal total cholesterol level
  • Reduced low-density lipoprotein cholesterol level

Brain MRI findings

• Hypoplastic corpus callosum
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes
• Optic nerve hypoplasia

Establishing the Diagnosis

The diagnosis of SQSD is established in a proband with gas chromatograph - mass spectroscopy (GC-MS) or nuclear magnetic resonance spectroscopy (NMRS) of urine metabolites showing the characteristic profile of SQSD (see Table 1) OR confirmed by identification of biallelic pathogenic variants in FDFT1 by molecular genetic testing (see Table 2).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of squalene synthase deficiency may be broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of squalene synthase deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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, structural brain malformations, cortical visual impairment, optic nerve hypoplasia, profound developmental delay, dry skin with photosensitivity, and genital malformations. The following information is based on three known affected individuals, two of whom are sibs [Coman et al 2018].

Neonates may present with the following features:

• Small for gestational age, including one individual with a birth weight at the tenth centile and another with an occipital frontal circumference at birth at the tenth centile
• Generalized seizures, typically presenting in the first week of life
• Neonatal hepatitis consisting of unconjugated hyperbilirubinemia and elevated liver function enzymes with normal hepatic synthetic function

Dysmorphic features may include the following (see Coman et al 2018):

• Coarse facial features
• Narrow forehead
• Epicanthus
• Depressed nasal bridge
• Low-set and posteriorly rotated ears
• Squared nasal tip
• Micrognathia and retrognathia
• 2-3 toe syndactyly

Neurologic findings may include the following:

• Generalized tonic-colonic seizures that present in the neonatal period
• Profound developmental delay. The limited number of affected individuals identified to date have been:
  • Able to sit independently
  • Nonambulatory
  • Nonverbal
  • Not able to perform any self-care
  Affected individuals have varying degrees of nonverbal social communication skills ranging from no meaningful nonverbal communication/interactions to use of eye contact.
• Autistic features
• Habitual eye poking
• Irritability
• Central hypotonia, typically present at birth
• Hyperreflexia, typically present at birth
• Hypersalivation

Brain MRI findings are often nonspecific but may include the following:

• Hypoplastic corpus callosum in two sibs
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes in one affected individual

Ophthalmology. Optic nerve hypoplasia was found in two affected sibs but was absent in one unrelated affected individual. However, all three affected individuals had cortical visual impairment.

Cardiac. Bicuspid aortic valve has been described in one affected individual. It is unclear if this is a finding within the spectrum of squalene synthase deficiency or an unrelated co-occurrence.

Sleep. All three affected individuals have been described as having delayed sleep initiation. One affected individual also had poor nocturnal sleep maintenance.

Gastrointestinal. All three affected individuals had postnatal failure to thrive and required placement of a gastrostomy tube to address dysphagia and poor growth. All three also had constipation, possibly secondary to hypotonia.

Genitourinary. One affected male had bilateral cryptorchidism and the other had hypospadias without cryptorchidism. The third affected individual is female without any known genitourinary anomalies.

Musculoskeletal. Skeletal radiographs demonstrated:

• Thin gracile bones in two sibs
• Reduced bone mineralization in two sibs
• Fixed flexion joint contractures at the knees in two sibs and of the elbows in one unrelated affected individual

Skin. All three affected individuals have dry skin with photosensitivity. The two sibs both had lack of hair pigmentation on microscopy.

Biochemical findings include the following:

• Plasma total cholesterol is mildly decreased.
• Plasma HDL- and LDL-cholesterol levels are decreased or low normal range.
• Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) are significantly increased.
• Plasma squalene levels are reduced or normal.
• Pathognomonic urine metabolic profile (See Suggestive Findings, Laboratory findings.)

Genotype-Phenotype Correlations

Thus far, pathogenic variants have included a contiguous gene deletion, a splice acceptor site variant, and an intronic deletion in three individuals with similar features. Therefore, no clear genotype-phenotype correlations exist.

Prevalence

The prevalence is unknown. Currently three affected individuals from two kindreds have been described [Coman et al 2018]. Both families are of European descent.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with squalene synthase deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There are currently no specific disease modifying treatments for SQSD.