DISEASE CARD

Disease group Keratinization Disorder
DISEASE NAME SJOGREN-LARSSON SYNDROME
Synonymous SLS, congenital ichthyosiform erythroderma, fatty aldehyde dehydrogenase deficiency
Estimated prevalence < 0.4:100,000
OMIM 270200
Inheritance Autosomal recessive
Gene (s) ALDH3A2 (609523)

Definition

Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder characterized by the clinical triad of congenital ichthyosis, mental retardation and spasticity due to deficiency of fatty aldehhyde dehydrogenase (FALDH) caused by mutation in ALDH3A2 gene.

Clinical Description

Skin involvement can be seen as early as 23 weeks of gestation. SLS-patients tend to be born preterm. At birth they present with generalized ichthyosis resembling lamellar ichthyosis or congenital ichthyosiform erythroderma, but usually without a collodion membrane. The skin is mildly erythematous and over time ichthyosis becomes most prominent in the flexural areas, nape of the neck, trunk and extremities here often with confluent hyperkeratotic papules having a cobblestone-like appearance rather than presenting with small white scales. There can be intensive pruritus. Neurological symptoms develop within the first two years of life going along with a developmental delay in motor and cognitive functions. Progressive spasticity leads to di- or tetraplegia with contractures, preventing or impairing the ability to walk in most SLS patients. Mental retardation is profound with two thirds of the patients having an IQ of less than 50. Additional clinical features include retinal crystalline inclusions surrounding the fovea (so-called glistening white dots), photophobia, myopia, seizures, short stature and speech defects of various kinds. Most patients live well into adulthood.

Pathogenesis

SLS is caused by mutation in ALDH3A2 gene on chromosome 17p11.2 encoding the 485 amino acids large enzyme FALDH. More than 72 different mutations have so far been identified representing at least 121 families around the world. Most frequent are missense mutations (38%). Although mutations are usually private, a few common mutations in Europe, Mideast and Brazil have been found such as c.943C>T, c.1297_1298delGA, c.682C>T, c.551C>T, c.733G>A, c.798+1delG. FALDH is part of the fatty alcohol:nicotinamide-adenine dinucleotide (NAD+)-oxidoreductase complex (FAO) necessary for the oxidation of long-chain aliphatic aldehydes to fatty acid. It belongs to the class-3 enzymes of a large ALDH family with a microsomal localization. It preferentially catalyses 16-20 carbons, additionally oxidizes branched-chain aliphatic aldehydes and is involved in w-oxidation of eicosanoids like leukotriene B4 (LTB4). SLS-patients have a deficiency in FALDH, and subsequently in FAO leading to an elevation of longchain alcohols in plasma and tissue cells. The exact pathophysiologic mechanism between the enzyme deficiency and the development of clinical symptoms is currently not understood. One speculates that either accumulation of fatty alcohols leads to biosynthesis of wax esters, which interfere with other lipids in the formation of lamellar bodies, or that an impaired synthesis of 20-COOH-(R)-TXA3 results in a decreased synthesis of (r)-hepoxilin-A3, which is also involved in 12R-LOX- or eLOX3-deficiency related lamellar ichthyosis.

Diagnosis

The patient's history includes a detailed family history. Main symptom that brings the newborn to medical attention is the generalized ichthyosiform erythroderma. Later the cobblestone appearance of hyperkeratotic papules helps to differentiate SLS from other forms of ichthyosis. Diagnosis becomes obvious when neurologic symptoms particularly spasticity appear. Proof of glistening dots is pathognomic for SLS. Histology is unspecific with striking hyperkeratosis, papillomatosis, acanthosis and slight upper-dermal inflammation. Histochemical staining for FAO is possible and reveals a reduction of FAO in a fresh SLS-skin biopsy thus demonstrating FALDH deficiency. Highly conclusive and valuable is the measurement of FALDH or FAO activity in cultured fibroblasts, keratinocytes or leukocytes by fluorometric or gas chromatography-mass spectrometry assays. DNA-based diagnosis is possible either by screening for common mutations or sequencing the entire gene. Brain MRI reveals white matter disease and MR spectroscopy demonstrates an unusual lipid peak in myelin. Prenatal diagnosis is possible via amniocentesis of chorionic villus sampling.

Treatment

To date, there is no causative therapy available. Non-specific approaches to treat ichthyosis are topical application of keratolytic agents, regular bath e.g. with sodium bicarbonate or oil followed by rubbing of soaked scales. Systemic retinoids can be tried. Seizures respond to anti-convulsant medications, and contractures due to spasticity needs surgical intervention. Special diets with supplementing medium-chain fatty acids have been suggested by some authors, but overall longterm benefits are questionable. Zileuton, an inhibitor of LTB4 synthesis seems to help ameliorating the disturbing pruritus. A new approach is directed to stimulate ALDH3A2 transcription by bezafibrate, a peroxisome proliferator-activated receptor alpha agonist, which has been shown to increase residual FALDH enzyme activity in SLS-fibroblasts.Many affected individuals as well as their families benefit from a contact with the self support group.