DISEASE CARD

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.¹

Clinical Description

Skin involvement can be seen as early as 23 weeks of gestation. Preterm birth is common in patients with STS (> 70%), presumably due to abnormal lipid metabolism.² A generalized ichthyosis manifests at birth or within the first months of life, resembling lamellar ichthyosis or congenital ichthyosiform erythroderma, but usually without a collodion membrane. The skin is mildly erythematous. With time the hyperkeratosis / ichthyosis becomes most prominent in the flexural areas, nape of the neck, trunk and extremities. Typical are confluent hyperkeratotic papules having a cobblestone-like appearance rather than small white scales. The associated pruritus can be very intensive.³

Neurological symptoms develop within the first two years of life, including developmental delay in motor function and mild to moderate cognitive deficits (developmental age mostly 5-6 years of age). Speech difficulties, and dysarthria are common as well. ^{3, 4} Rarely a severe phenotype goes along with an unexpected loss of neurologic functions later in life, associated with physical stressors.⁵  

Progressive spasticity leads to di- or (rarely) tetraplegia with contractures, preventing or impairing the ability to walk in most SLS patients.

Ophthalmologic involvement is frequent, and mostly due to retinal crystalline inclusions surrounding the fovea (so-called glistening white dots). This sign might not be present in every patient but is a pathognomonic feature of the disease, when present. ⁶ Additional symptoms include photophobia, myopia, seizures (in 35-40%), leukoencephalopathy and short stature. Most patients live well into adulthood.⁷

Pathogenesis

SLS is caused by mutation in ALDH3A2 gene on chromosome 17p11.2 encoding the 485 amino acids large enzyme FALDH. ⁸ More than 72 different mutations have so far been identified representing at least 121 families around the world. Most frequent are missense mutations (38%).⁹ 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.^{8, 10}

ALDH 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.¹¹ It has been shown that fatty alcohols of unusually long chain length (C18-C24) together with their corresponding ether lipid synthesis products accumulate in brain tissue. ²

Diagnosis

The patient's history includes a detailed family history. 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 of the entire FALDH gene. Brain MRI reveals white matter disease and MR spectroscopy demonstrates an unusual lipid peak in myelin.¹² Prenatal diagnosis is possible via amniocentesis of chorionic villus sampling.

Treatment

To date, there is no causative therapy available. Approaches to treat ichthyosis include topical application of keratolytic agents, regular bathing e.g. with sodium bicarbonate or oil followed by rubbing of soaked scales. Systemic retinoids can be used but are limited because of their side effects. 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 not clear. Zileuton, an inhibitor of LTB4 synthesis seems to help ameliorating the disturbing pruritus.¹³ 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.^{11, 14} In order to optimize the speech-language development, early intervention is recommended

References

^{1. Sjogren T. Oligophrenia combined with congenital ichthyosiform erythrodermia, spastic syndrome and macularretinal degeneration; a clinical and genetic study. Acta Genet Stat Med. 1956;6(1 Part 2):80-91.}

^{2. Staps P, Hogeveen M, Fuijkschot J, van Drongelen J, Willemsen M. Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model. J Perinat Med. 2018;46(5):523-529.}

^{3. Fuijkschot J, Theelen T, Seyger MM, et al. Sjögren-Larsson syndrome in clinical practice. J Inherit Metab Dis. 2012;35(6):955-962.}

^{4. Willemsen MA, L IJ, Steijlen PM, et al. Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome. Brain. 2001;124(Pt 7):1426-1437.}

^{5. Warrack S, Love T, Rizzo WB. A Neurodegenerative Phenotype Associated With Sjögren-Larsson Syndrome. 2021;36(11):1011-1016.}

^{6. Willemsen MA, Cruysberg JR, Rotteveel JJ, Aandekerk AL, Van Domburg PH, Deutman AF. Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome. Am J Ophthalmol. 2000;130(6):782-789.}

^{7. Bindu PS. Sjogren-Larsson Syndrome: Mechanisms and Management. Appl Clin Genet. 2020;13:13-24.}

^{8. Rizzo WB, Carney G, De Laurenzi V. A common deletion mutation in European patients with Sjögren-Larsson syndrome. Biochem Mol Med. 1997;62(2):178-181.}

^{9. Rizzo WB, Carney G. Sjögren-Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mutat. 2005;26(1):1-10.}

^{10. De Laurenzi V, Rogers GR, Tarcsa E, et al. Sjögren-Larsson syndrome is caused by a common mutation in northern European and Swedish patients. J Invest Dermatol. 1997;109(1):79-83.}

^{11. Rizzo WB. Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metab. 2007;90(1):1-9.}

^{12. Willemsen MA, Van Der Graaf M, Van Der Knaap MS, Heerschap A, Van Domburg PH, Gabreëls FJ, Rotteveel JJ. MR imaging and proton MR spectroscopic studies in Sjögren-Larsson syndrome: characterization of the leukoencephalopathy. AJNR Am J Neuroradiol. 2004 Apr;25(4):649-57.} 

^{13. Willemsen MA, Lutt MA, Steijlen PM, et al. Clinical and biochemical effects of zileuton in patients with the Sjögren-Larsson syndrome. Eur J Pediatr. 2001;160(12):711-717.}

^{14. Gloerich J, Ijlst L, Wanders RJ, Ferdinandusse S. Bezafibrate induces FALDH in human fibroblasts; implications for Sjögren-Larsson syndrome. Mol Genet Metab. 2006 Sep-Oct;89(1-2):111-5.} 

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