Genetics of Sjogren-Larsson Syndrome Workup

Updated: Mar 06, 2023
  • Author: William B Rizzo, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Laboratory Studies

The definitive test for Sjögren-Larsson syndrome (SLS) is measurement of FALDH or fatty alcohol:NAD oxidoreductase in cultured skin fibroblasts. Patients with Sjögren-Larsson syndrome have less than 15% of the activity found in individuals without the condition. Heterozygous carriers for Sjögren-Larsson syndrome typically have one half of the activity seen in individuals without any gene for the syndrome; however, some carriers overlap the lower end of the reference range.

The drawbacks to enzymatic testing of fibroblast cultures include the need for an invasive skin biopsy, requirement for a referral laboratory to grow the cells which typically requires 3-6 weeks, and the limited availability of diagnostic laboratories to perform the testing. However, skin fibroblasts afford a renewable source of patient material for biochemical testing and can be used as a source of DNA for mutation analysis.

DNA tests can detect mutations in the ALDH3A2 gene and are considered a diagnostic test of choice. [6] A few mutations are commonly observed in patients from Europe, the Middle East and Brazil, but most mutations are specific for single families and may require sequencing the entire gene to detect them.

After the mutations in a particular family are identified, targeted mutation screening is more convenient than enzyme studies for confirming the diagnosis of Sjögren-Larsson syndrome in other affected family members; it also obviates the need for an invasive skin biopsy to grow fibroblast cultures for enzymatic testing.

Once the mutation is identified in a patient with Sjögren-Larsson syndrome, DNA analysis is the most reliable test for detecting genetic carriers in the family.

DNA for mutation screening can be obtained from blood or noninvasively collected from a buccal swab or saliva specimen. Using conventional methods for sequencing exons amplified from genomic DNA, at least 95% of the mutations that cause SLS can be identified. However, a few mutations can be missed, including certain splicing defects, duplications of one or more exons, and certain promoter or intronic mutations. In those instances, studies of RNA splicing and expression in cultured fibroblasts may be useful.

Sjögren-Larsson syndrome can also be diagnosed by directly demonstrating defective fatty alcohol oxidation in a skin-biopsy sample using a histochemical staining method. This approach is not quantitative. Other methods for diagnosing Sjögren-Larsson syndrome, such as demonstration of elevated plasma fatty alcohols or urinary leukotriene B4 excretion, lack specificity and have not been adopted for routine clinical use.

The usual metabolic screening tests (eg, serum amino acids, urine organic acids, urine metabolic screens) are of no diagnostic value.

Routine blood tests (eg, for electrolytes, transaminases, renal function, CBC count) reveal results within reference ranges.


Imaging Studies

Brain MRI is useful for detecting white-matter disease, which is observed in most patients with Sjögren-Larsson syndrome. [12] The myelin abnormality usually involves the periventricular regions, the centrum semiovale, the corpus callosum, and frontal and parietal lobes. In infants with Sjögren-Larsson syndrome, initial MRI findings may appear normal, with evidence of white-matter disease emerging later, as the patient ages.

Proton magnetic resonance spectroscopy of the brain often reveals an unidentified peak in the lipid region of the spectrum. The specificity of this lipid peak in those with Sjögren-Larsson syndrome is yet to be determined.


Other Tests

Electrophysiologic studies help define the extent of neurologic disease.

Somatosensory-evoked potentials and brainstem auditory-evoked potentials are outside the reference ranges in some patients with Sjögren-Larsson syndrome, but nerve conduction velocities are typically within the reference range. [32]

Optical coherence tomography is useful procedure to detect early evidence of cystoid foveal degeneration associated with Muller cell degeneration in the retina of patients. [33]



Skin biopsy is frequently performed in patients with Sjögren-Larsson syndrome to examine the histopathology of the skin; this is useful for diagnosing certain forms of ichthyosis. Skin biopsy should be performed to establish fibroblast cultures for enzymatic testing.


Histologic Findings

A skin biopsy examined under light microscopy typically shows hyperkeratosis, papillomatosis, and a somewhat thickened granular layer. However, these histologic changes are not diagnostic for Sjögren-Larsson syndrome because they are observed in other forms of ichthyosis.

Ultrastructural analysis of the skin reveals abnormal lipid inclusions in the cytoplasm of the granular cells and in the stratum corneum, and defective lamellar bodies in the granular keratinocytes. [34, 23] The intercellular membranes of the stratum corneum are depleted and show nonlamellar lipid inclusions. Lamellar bodies are not secreted properly and become entombed in the corneocytes of the stratum corneum.