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Last updated:
May 09, 2019
Years published: 1988, 1989, 1992, 1993, 1995, 1997, 1999, 2004, 2019
NORD gratefully acknowledges Karen Wernke, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Summary
Sjögren-Larsson syndrome (SLS) is an inherited disorder characterized by scaling skin (ichthyosis), intellectual disability, speech abnormalities, and spasticity. Affected infants develop various degrees of reddened skin with fine scales soon after birth. After infancy, the skin loses its redness and dark scales often appear on the neck and under the arms. Additionally, larger plate-like thick scales may develop on the lower legs. Developmental delay, speech abnormalities and seizures may accompany skin symptoms. Spasticity in the legs typically impairs motor ability and walking. Many children with this disorder have glistening white dots or degeneration of the pigment in the retina of the eye.
Introduction
SLS was first described in 1957 by Swedish physicians, Sjögren and Larsson. They reported a group of 28 interrelated patients from Vasterbotten County, Sweden, who had symptoms of what is now thought of as the clinical triad, or diagnostic signs, of Sjögren-Larsson syndrome: intellectual disability, muscle stiffness in the legs (spastic diplegia), and scaly skin from birth (congenital ichthyosis). SLS is a type of leukodystrophy, which are rare, progressive, metabolic, genetic diseases that affects the brain, spinal cord and often the peripheral nerves.
The first sign of Sjögren-Larsson syndrome is often preterm birth. Apparent at birth, the ichthyosis associated with SLS often starts as thickened skin that is yellow-brown in color (hyperkeratosis). This thickened skin eventually progresses to full scaling, especially at the neck, lower abdomen, and underarms, groin, and back of knees (flexures). Unique to SLS is the itchy characteristic of the skin (pruritis).
The second feature of SLS is the stiffening of the muscles (spastic paresis). This affects the legs more often than the arms. Some individuals with SLS can walk without support, but as the stiffening worsens over time many individuals opt to use a wheelchair.
The other main clinical feature of SLS is intellectual disability. Most patients reach an average developmental age of 5-6 years of age.
Other features that could be seen include seizures, speech difficulty, short stature, spinal abnormalities (kyphoscoliosis), smaller head and brain (microcephaly), numbness in the hands and feet (peripheral neuropathy), widely spaced teeth, under-formed enamel of the teeth, widely spaced eyes, and uncontrolled movements of the eyes (nystagmus).
The symptoms of the condition can vary, even within families. However, scaling skin (ichthyosis), intellectual disability, and muscle stiffness (spastic paresis) are always seen. The average lifespan for affected males and females is 15 years and 26 years, respectively.
The gene that is altered in patients with Sjögren-Larsson syndrome is the aldehyde dehydrogenase 3A2 (ALDH3A2) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Changes (mutations) in the ALDH3A2 gene result in a lower than normal amount of an enzyme (fatty aldehyde dehydrogenase). A lower amount of this enzyme leads to the scaly and itchy skin and other features seen in Sjögren-Larsson syndrome.
SLS is an autosomal recessive condition. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Sjögren-Larsson syndrome affected both males and females equally and its onset is from birth. The incidence of this condition worldwide is unknown. However, the prevalence in Sweden is 1 in every 250,000 individuals.
A diagnosis of Sjögren-Larsson syndrome may be suspected at birth. A clinical diagnosis can be made by age 3 when the primary features of the disorder are usually apparent. The affected individual usually does not have a family history of this disease.
Clinical Testing and Work-Up
Following a clinical suspicion of SLS, molecular genetic testing can be performed to look for mutations in the ALDH3A2 gene. 95% of patients have two mutations in this gene, leading to the symptoms seen in Sjögren-Larsson syndrome.
Biochemical testing could also be ordered when suspecting SLS. However, it is very difficult to confirm a diagnosis of SLS at this level, and genetic testing is the more definitive means of making a diagnosis.
Treatment
There is no cure for Sjögren-Larsson syndrome. Treatment focuses on treating symptoms as they appear and may require multiple different specialists to help address them. A comprehensive team to care for children with SLS might include specialists who help with problems of the brain and central nervous system (neurologists), specialists who assess and treat problems with the skin (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), and specialists who help with movement problems (physiotherapists).
Diets low in long-chain fats, such as oils, fish, nuts, avocados, and meat, and supplemented with medium-chain fats (triglycerides), such as dairy products and coconut oil, have been associated with skin improvement for some patients. Other means of diminishing scaling of the skin includes applying keratolytic or urea-containing lotions or creams.
While there is no cure for the muscle stiffness, physical therapy may help with movement. Other means in assisting movement might include bracing and support.
Individuals with SLS will likely benefit from special education services in light of their intellectual disability. Speech and language therapy has shown some benefit in improving language performance and augmented communication skills.
Genetic counseling is recommended for affected individuals and their family members.
The drug zileuton has been used to improve the itchy characteristic of the skin (pruritis) and improved behavior in a few affected individuals. Its use is warranted when the itching is severe and the individual is over 5 years of age.
Bezafibrates are useful for affected individuals who have residual FALDH expression. One study has shown improved FALDH activity in fibroblasts from affected patients. This therapy requires further study to demonstrate additional benefits.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Dutra LA, Braga-Neto P, Pedroso JL, Barsottini OGP. Sjögren-Larsson Syndrome. In: Ahmad S, ed. Neurodegenerative Diseases. 1st ed. New York, NY: Springer; 2012:344-349.
JOURNAL ARTICLES
Nagappa M, Bindu P, Chiplunkar S, et al. Child Neurology: Sjögren-Larsson syndrome. Neurology. 2017;88(1): e1-e4. doi: 10.1212/WNL.0000000000003456.
Rizzo WB. Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. Expert Opinion on Orphan Drugs. 2016;4(4): 395-406.
Yoneda K. Inherited Ichthyosis: Syndromic Forms. Journal of Dermatology.2016;43: 252-263.
Fuijkschot J, Theelen T, Seyger MM, et al. Sjögren-Larsson syndrome in clinical practice. J Inherit Metab Dis. 2012;35: 955-962.
Fuijkschot J, Maassen B, Gorter JW, Gerven MV, Willemsen M. Speech-language performance in Sjögren-Larsson syndrome. Developmental Neurorehabilitation. 2009;12(2): 106-112.
Gordon N. Sjögren-Larsson syndrome. Developmental Medicine & Child Neurology. 2007;49: 152-154.
Rizzo WB. Sjögren-Larsson Syndrome: Molecular Genetics and Biochemcial Pathologenesis of Fatty Aldehyde Dehydrogenase Deficiency. Mol Genet Metab. 2007;90(1): 1-9.
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