Sjögren-Larsson syndrome

Synonyms

7

Overview

Sjogren-Larsson syndrome is an inborn error of lipid metabolism, characterized by congenital ichthyosis (dry, scaly skin), intellectual disability, and spasticity (stiffness and involuntary muscle spasms). These symptoms are apparent by early childhood and usually do not worsen with age. SLS is an autosomal recessive form of ichthyosis apparent at birth. Sjögren–Larsson syndrome is a rare autosomal, recessive, neurocutaneous disease. This disease can be identified by a triad of medical disorders. The first is ichthyosis, which is a buildup of skin to form a scale-like covering that causes dry skin and other problems. The second identifier is spastic paraplegia which is characterized by leg spasms. The final identifier is intellectual delay. The gene of SLS is found on chromosome 17. In order for a child to receive SLS both parents must be carriers of the SLS gene. If they are carriers their child has a ¼ chance of getting the disease. In 1957 Sjogren and Larsson proposed that the Swedes with the disease all descended from a common ancestor 600 years ago. Today only 30-40 persons in Sweden have this disease.

Affected infants tend to be born prematurely. At birth the skin is red (erythema), but later in infancy the skin becomes dry, rough, and scaly with a brownish or yellowish tone. Mild to severe itchiness (pruritus) is also common. These skin abnormalities are generally dispersed over the whole body, most severely affecting the nape of the neck, the torso, and the extremities. The skin of the face is usually not affected.

People with this condition may also have neurological signs and symptoms. Most affected individuals have leukoencephalopathy, which is a change in a type of brain tissue called white matter. White matter consists of nerve fibers covered by a substance (myelin) that insulates and protects the nerves. The leukoencephalopathy is thought to contribute to many of the neurological signs and symptoms in people with Sjögren-Larsson syndrome. Most affected individuals have intellectual disability that varies from mild to profound and is usually apparent by early childhood. People with Sjögren-Larsson syndrome have speech difficulties (dysarthria) and delayed speech. Usually they are able to produce only short sentences with poorly formed words. Rarely, people with this condition have normal intelligence. In addition, approximately 40 percent of people with Sjögren-Larsson syndrome have seizures.

Children with this condition often experience delayed development of motor skills (such as crawling and walking) due to abnormal muscle stiffness (spasticity) that is typically in their legs and, less commonly, also in their arms. About one-half of people with Sjögren-Larsson syndrome require wheelchair assistance and many others need some form of support to walk.

Affected individuals have tiny crystals in the light-sensitive tissue at the back of the eye (retina) that can be seen during an eye exam. Based on their appearance, these retinal crystals are often called glistening white dots. These white dots are usually apparent by early childhood, and it is unclear if they affect normal vision. People with Sjögren-Larsson syndrome may also have nearsightedness (myopia) or an increased sensitivity to light (photophobia).

Symptoms

The signs and symptoms of SLS typically occur within the first two years of life. A primary feature of SLS is dry, scaly skin, which is called ichthyosis. In addition to ichthyosis, people can develop some or all of the following symptoms:

  • Developmental delay
  • Mental retardation
  • Speech difficulties
  • Seizures
  • Spastic diplegia/tetraplegia paralysis (diplegia is paralysis of both legs; tetraplegia is paralysis of all four limbs)
  • Spasticity in the legs: leg spasms, which can impair motor abilities and waking
  • Glistening white dotes in the retina of the eye
  • Pruritis (itching)
  • Preterm birth
  • Neurological disorders 
  • Stiff leg movements 
  • Awkward leg movements 
  • Stiff arm movements 
  • Awkward arm movements
  • Thin hair
  • Brittle hair 
  • Thickening of skin on face 
  • Thickening of skin on scalp 
  • Scaly ichthyosis 
  • Skin redness 
  • Thickening of skin on palms 
  • Thickening of skin on soles 
  • Macular lesions 
  • Recurring corneal ulceration 
  • Increased deep tendon reflexes of the legs 
  • Ankle clonus 
  • Babinski sign 
  • Mildly increased arm reflexes 
  • Hydrocephalus 
  • Sclerotic cortical atrophy

Note that Sjögren-Larsson syndrome symptoms usually refers to various symptoms known to a patient, but the phrase Sjögren-Larsson syndrome signs may refer to those signs only noticable by a doctor.

Causes

SLS is caused mutations in the FADH (fatty aldehyde dehydrogenase) gene, which is located on chromosome 17 on the p arm at band 11.2. The enzyme made by the FADH gene is responsible for breaking down certain molecules called medium- and long-chain fatty aldehydes. If FADH is not functioning properly, these and related molecules build up in the body, specifically the membranes of the skin and brain, leading to the symptoms associated with SLS.

Mutations in the ALDH3A2 gene cause Sjögren-Larsson syndrome. The ALDH3A2 gene provides instructions for making an enzyme called fatty aldehyde dehydrogenase (FALDH). The FALDH enzyme is part of a multistep process called fatty acid oxidation in which fats are broken down and converted into energy. Specifically, the FALDH enzyme breaks down molecules called fatty aldehydes to fatty acids.

Diagnosis

SLS can be diagnosed by a biochemical blood test that determines if FADH activity is normal. In addition, because mutations in FADH are known to cause SLS, the gene can be sequenced in order to determine if any mutations are present. This also provides the option of genetic and prenatal testing, which can allow parents to make informed decisions about having children.

Treatment

Topical application of various agents have been used to treat the ichthyosis. Some clinical studies have found that a drug called zileuton can be beneficial in the treatment of SLS. In these studies, the drug successfully reduced the severity of the pruritis (itching), and improved the behavior of the treated child. While this drug does not cure SLS, it has the potential to greatly improve the quality of life of children with SLS. Seizures usually respond well to anti-convulsant medications and spasticity is improved with surgery. Diets supplemented with medium-chain fatty acids have been reported to improve the skin, but the results are inconsistent.

Resources

  • NIH
  • Genetics Home Reference