Sjögren-Larsson syndrome (ORPHA:816)
A rare neurocutaneous disorder caused by an inborn error of lipid metabolism and characterized by congenital ichthyosis, intellectual deficit, and spasticity.
Epidemiology
Prevalence is estimated at 1/250,000 worldwide, but the syndrome is more common in Sweden due to a founder effect.
Clinical description
Clinical features develop perinatally and during infancy. Patients tend to be born preterm. Hyperkeratosis is usually present at birth and progresses to a generalized ichthyosis, particularly prominent on flexural areas, the nape of the neck, the trunk and the extremities. Pruritus is a prominent feature. Erythematous dermatitis is often present at birth, and then tends to fade with increasing age. Neurological signs appear during the first two years of life and consist of delay in reaching motor milestones due to spastic diplegia or, much less commonly, spastic tetraplegia. Approximately one-half of patients are non-ambulatory. Seizures occur in about 40% of cases. Intellectual deficit varies from mild to severe, although rare patients with normal intellect have been reported. Delayed speech and dysarthria are common. Ophthalmologic involvement is often present and is characterized by retinal crystalline inclusions (so-called glistening white dots) surrounding the fovea. Photophobia and myopia are common.
Etiology
SLS is caused by mutations in the ALDH3A2 gene (17p11.2) encoding fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehydes to fatty acids. More than 90 mutations in ALDH3A2 have been identified, including amino acid substitutions, deletions, insertions, splicing errors and contiguous gene deletions.
Diagnostic methods
SLS is diagnosed based on the clinical features, and by measuring FALDH or fatty alcohol oxidoreductase (FAO) activity in cultured fibroblasts from skin biopsies. DNA-based diagnosis is possible by directly sequencing the ALDH3A2 gene and identifying pathogenic mutations.
Differential diagnosis
In early infancy, before the onset of spasticity, the differential diagnosis includes other forms of congenital ichthyosis including lamellar ichthyosis and congenital ichthyosiform erythroderma. Once neurologic symptoms appear, the differential diagnosis includes other neuro-ichthyotic syndromes such as neutral lipid storage disease (Chanarin-Dorfman syndrome), ELOVL4 deficiency, multiple sulfatase deficiency and Refsum disease.
Antenatal diagnosis
Antenatal diagnosis is possible through biochemical or molecular analysis of amniocytes or chorionic villus cells.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management should be multidisciplinary including neurologists, dermatologists, ophthalmologists, orthopedic surgeons, and physiotherapists. The treatment of ichthyosis consists of topical application of moisturizing creams and keratolytic agents, or use of systemic retinoids. Seizures usually respond to anti-convulsant medications and spasticity is alleviated by botulinum toxin injections or surgical procedures. Special diets with medium-chain fatty acid supplements may help the ichthyosis, but effects are limited.
Prognosis
Patients usually survive until adulthood but require life-long care. Minimal progression of the neurologic findings or intellectual deficit occurs after puberty. Patients with early symptoms tend to be more severely affected.

                            Last update: 
                            October 2019


                            - Expert reviewer(s): 
                            Dr William RIZZO