Practice Essentials
In 1957, Sjögren and Larsson described a cohort of Swedish patients with an unusual combination of symptoms that included of congenital ichthyosis, intellectual disability, and spastic diplegia or tetraplegia. [1] Family studies indicated that Sjögren-Larsson syndrome (SLS) was a genetic disorder with autosomal recessive inheritance. Similar patients of all ethnic origins were subsequently recognized throughout the world. [2]
Two decades later, Sjögren-Larsson syndrome was shown to be an inborn error of lipid metabolism caused by deficient activity of fatty alcohol:NAD oxidoreductase. [3] Subsequent studies identified a defect in fatty aldehyde dehydrogenase (FALDH), a component of the fatty alcohol:NAD oxidoreductase enzyme complex. [4] The FALDH gene (renamed ALDH3A2) was cloned in 1996, and patients with Sjögren-Larsson syndrome were found to have mutations in this gene. [5, 6] Enzymatic and genetic testing provide a reliable means for diagnosing Sjögren-Larsson syndrome and determining carrier status. [7] Sjögren-Larsson syndrome is now the most widely recognized form of neuroichthyosis.
Signs and symptoms of Sjögren-Larsson syndrome
Ichthyosis is apparent upon physical examination in almost all patients with Sjögren-Larsson syndrome. [8, 7, 9] The ichthyosis has a generalized distribution and is usually prominent on the trunk, extremities, flexures, axilla, nape of the neck, and back.
Spasticity is almost always present by age 2 years. [10] Spastic diplegia is much more common than spastic tetraplegia in individuals with this disorder. In infants with Sjögren-Larsson syndrome, hypertonia is the most common neurologic finding on physical examination.
Intellectual disability varies from profound to mild; in most patients with Sjögren-Larsson syndrome, it is mild to moderate, and rare patients have little cognitive impairment. [7]
Ophthalmologic findings include glistening white dots that affect the retina and retinal pigmentary changes. [11]
Short stature is common owing to a combination of growth delay and leg contractures.
Workup in Sjögren-Larsson syndrome
Laboratory studies
The definitive test for Sjögren-Larsson syndrome 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.
DNA tests can detect mutations in the ALDH3A2 gene and are considered a diagnostic test of choice. [6]
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.
Imaging studies
Brain magnetic resonance imaging (MRI) is useful for detecting white-matter disease, which is observed in most patients with Sjögren-Larsson syndrome. [12]
Management of Sjögren-Larsson syndrome
Systemic retinoids markedly benefit ichthyosis; however, they are infrequently used in children because of concern about potential adverse effects (eg, growth delay due to epiphyseal closure).
Patients with severe pruritus may benefit from treatment with zileuton, which blocks the synthesis of leukotriene B4, a compound that, along with its omega-hydroxy metabolite, probably gives rise to the itching. [13] Seizures, if recurrent, usually respond to standard anticonvulsant medications.
Spasticity in patients with Sjögren-Larsson syndrome is often improved by surgical procedures (eg, tendon lengthening, adductor release, dorsal root rhizotomy). [14] These procedures may help some patients with the syndrome become ambulatory.
Including physical therapy in the care of patients with Sjögren-Larsson syndrome is important to prevent or mitigate leg contractures that naturally develop in this disease.
Pathophysiology
The genetic defect in Sjögren-Larsson syndrome results in deficient activity of FALDH, which catalyzes the oxidation of fatty aldehyde to fatty acid. [15] New insight into the pathogenesis of Sjögren-Larsson syndrome is emerging from knowledge about the metabolic role of this enzyme. [16] FALDH acts on fatty aldehydes derived from metabolism of fatty alcohol, [3] phytanic acid (a branched-chain fatty acid), [17] phytol (the alcohol precursor to phytanic acid), [18] ether glycerolipids, [19] and leukotriene B4. [20] Tissue dysfunction is thought to be due to lipid storage in membranes. [16] FALDH is a component of the fatty alcohol:NAD oxidoreductase enzyme complex that catalyzes the sequential oxidation of fatty alcohol to aldehyde and fatty acid. Therefore, patients with Sjögren-Larsson syndrome have deficient activity of FALDH and fatty alcohol:NAD oxidoreductase, which results in defective metabolism of both fatty aldehyde and fatty alcohol. [7]
In Sjögren-Larsson syndrome, FALDH deficiency impairs fatty alcohol oxidation and leads to accumulation of 16- and 18-carbon-long aliphatic alcohols. [21] In cultured skin keratinocytes, elevated fatty alcohol is diverted into the synthesis of wax esters and alkyldiacylglycerol lipids. [22] Accumulation of fatty alcohol and related lipid products disrupts formation of the intercellular membranes in the stratum corneum, which is critical for epidermal water barrier. [23] The skin attempts to reestablish a water barrier by making more stratum corneum, resulting in ichthyosis.
However, a study by Arai et al suggested that in Sjögren-Larsson syndrome, a primary source of ichthyosis is a decreased acylceramide level. The acylceramides, along with protein-bound ceramides, are essential factors in the development of the skin’s permeability barrier. In their evaluation of a patient with Sjögren-Larsson syndrome, the investigators found that all of her acylceramide classes from the stratum corneum were present in decreased concentrations, with the acylceramide levels being, in total, 75% below those of healthy controls. The study also found evidence that other, nonacylated ceramides may be involved in ichthyosis. [24]
In addition to their above-mentioned effects, fatty alcohol and aldehyde may alter the normal integrity of myelin membranes in the brain, leading to white-matter disease and spasticity. [16] FALDH is involved in the oxidation of fatty aldehydes produced by catabolism of ether glycerolipids (plasmalogens), which are prominent phospholipids in myelin. Accumulation of fatty aldehydes, which are highly reactive molecules, can form covalent Schiff-base derivatives with phosphatidylethanolamine, which may influence myelin membrane properties and alter the function of membrane-bound proteins. [25] Schiff-base aldehyde adducts with other amino-containing molecules, including key membrane enzymes and proteins, may also be detrimental to their function.
Patients with Sjögren-Larsson syndrome accumulate leukotriene B4 and its omega-hydroxy metabolite, which are probably responsible for the pruritus seen in this disease. [20] Furthermore, patients with this disorder have low levels of certain polyunsaturated fatty acids in plasma, which can contribute to the cutaneous and neurologic disease in Sjögren-Larsson syndrome.
The macular degeneration in Sjögren-Larsson syndrome is associated with fundal autofluorescence and a unique deficiency of retinal macular pigments, especially the carotinoid zeaxanthin. [26] This may reflect increased photo-oxidation and cellular toxicity with lipofuscin deposition in the retina.
Epidemiology
Frequency
United States
The incidence is not known.
International
The prevalence is estimated to be 0.4 cases per 100,000 people in Sweden. [9] The prevalence elsewhere is not known.
Mortality/Morbidity
Patients with Sjögren-Larsson syndrome usually survive well into adulthood. Life expectancy of those with Sjögren-Larsson syndrome is probably determined by the severity of neurologic symptoms and is comparable to that of other patients with static or slowly progressive neurologic disease. Morbidity is associated with chronic neurologic disease and lifelong ichthyosis.
Race
Sjögren-Larsson syndrome has been diagnosed in patients of all races.
Sex
Sjögren-Larsson syndrome is autosomal recessive. Male and female individuals are equally affected.
Age
Sjögren-Larsson syndrome is a genetic disease present from conception. Fetuses with Sjögren-Larsson syndrome have histologic evidence of ichthyosis as early as the end of the second trimester. Most infants with Sjögren-Larsson syndrome have cutaneous signs at birth; neurologic symptoms usually develop within 2 years. Symptoms persist throughout life.
