Sjögren-Larsson syndrome (SLS) is a rare genetic disorder characterized by a triad of features: congenital ichthyosis (dry, scaly skin present at birth), intellectual disability, and spastic diplegia or tetraplegia (stiffness and tightness in the muscles, affecting the legs more than the arms). The prevalence of SSL is estimated at 1 case per 250.000 population and is highest in Sweden.
Sjögren-Larsson syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
The key features and aspects of Sjögren-Larsson syndrome are:
- Genetic Basis: Sjögren-Larsson syndrome is caused by mutations in the ALDH3A2 gene. This gene provides instructions for producing an enzyme called fatty aldehyde dehydrogenase, which plays a role in lipid metabolism.
- Ichthyosis: The skin abnormality in SLS, known as congenital ichthyosis, leads to dry, scaly skin often present at birth. The severity of the skin condition can vary among individuals, and it may improve somewhat with age.
- Intellectual Disability: Individuals with Sjögren-Larsson syndrome typically have intellectual disability. The degree of intellectual impairment can vary from mild to moderate.
- Spastic Diplegia or Tetraplegia: Sjögren-Larsson syndrome is associated with spasticity in the muscles, affecting either the legs (spastic diplegia) or both the arms and legs (spastic tetraplegia). This can lead to stiffness, difficulty with movement, and walking difficulties.
- Ophthalmologic Abnormalities: Ophthalmologic features may include various eye abnormalities such as nystagmus (involuntary eye movements), strabismus (crossed eyes), and myopia (nearsightedness).
- Diagnosis: The diagnosis of Sjögren-Larsson syndrome is typically based on clinical features, including the triad of symptoms and genetic testing to identify mutations in the ALDH3A2 gene.
- Management: There is no cure for Sjögren-Larsson syndrome, and treatment focuses on managing symptoms and providing supportive care. This may involve skincare to address the ichthyosis, physical therapy to manage spasticity and improve mobility, and educational interventions for intellectual disability.
Sjögren-Larsson syndrome is an autosomal recessively inherited disorder due to mutations in the ALDH3A2 gene. This gene codes for the enzyme aldehyde dehydrogenase (FALDH), which catalyzes the oxidation of fatty aldehydes to fatty acids. About 90 pathogenic variants have been identified, including nucleotide substitutions, deletions, insertions, and transcriptional alterations. Cases have been reported in Europe, the Middle East, and Brazil.
The c.943C>T mutation (p.Pro315Ser) is a common pathogenic variant among patients of Swedish, Dutch, German and Belgian descent. It is known as the "Swedish variant" and has been observed in homozygosity and compound heterozygosity or combined with another mutation in ALDH3A2. It is the most frequent variant along with the small deletion c.1297_1298delGA (p. Glu433Argfs*3), which results in a reading frame shift, creating a premature stop codon, and results in a truncated protein with enzyme activity below 1%.
The c.551C>T (p.Thr184Met) mutation in the ALDH3A2 gene is also observed in patients with SSL in homozygosis and compound heterozygosis. This is a nonconservative substitution with effects on the secondary structure of the protein, resulting in a nearly afunctional enzyme whose activity is below 1%.
Some variants are less deleterious, such as c.798G>C (p.Lys266Asn), which partially affects FALDH enzyme activity and has been associated with less severe SSL phenotypes. However, not enough studies are available to establish a correlation between FALDH enzyme activity and symptomatology.
Sjögren-Larsson syndrome genetic testing analyzes the 8 most frequent pathogenic mutations of the ALDH3A2 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
