Abstract
Sjögren‐Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype‐phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.
Highlights
In 1957, Sjögren and Larsson described a syndrome with congenital ichthyosis, intellectual disability, and spastic diplegia, in a series of 28 Swedish patients with a rather homogeneous clinical phenotype, enabling the recognition of the disorder that has since been called SjögrenLarsson syndrome (SLS).[1]In 1988, it was found that abnormalities in the lipid metabolism were responsible for the clinical features of SLS.[2]
SYNOPSIS Sjögren-Larsson syndrome (OMIM #270200) is a recognizable clinical disorder that almost always leads to a severe phenotype; in this study, we learn that mild phenotypes exist, with the same genetic and biochemical abnormalities, and normal intelligence but otherwise essentially the same—but far less severe—neurocutaneous syndrome
We describe two adult patients with both biochemical and genetical confirmations of SLS, presenting with a milder spectrum of this disorder from the classical form
Summary
In 1957, Sjögren and Larsson described a syndrome with congenital ichthyosis, intellectual disability, and spastic diplegia, in a series of 28 Swedish patients with a rather homogeneous clinical phenotype, enabling the recognition of the disorder that has since been called SjögrenLarsson syndrome (SLS).[1]. ALDH3A2 mutations have been identified in all patients with SLS.[3] To date, more than 100 mutations in the ALDH3A2 gene have been described,[4] and all patients, except some extremely rare cases, appear to suffer from essentially the same, aforementioned clinical triad of symptoms, with only minor variations in severity.[5,6,7,8,9]. SYNOPSIS Sjögren-Larsson syndrome (OMIM #270200) is a recognizable clinical disorder that almost always leads to a (classic) severe phenotype; in this study, we learn that mild phenotypes exist, with the same genetic and biochemical abnormalities, and normal intelligence but otherwise essentially the same—but far less severe—neurocutaneous syndrome. By making comparisons between the mild vs classical presentation, we hope to identify the factors involved in determining the clinical outcome and understand the natural history, improving our insights into the underlying disease mechanism
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