AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

In 1957, Sjögren and Larsson described a cohort of Swedish patients with an unusual combination of symptoms that included of congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia.¹ Family studies indicated that Sjögren-Larsson syndrome (SLS) was a genetic disorder with autosomal recessive inheritance.² Similar patients of all ethnic origins were subsequently recognized throughout the world.

SLS was shown to be an inborn error of lipid metabolism caused by deficient activity of fatty alcohol:NAD oxidoreductase. Later studies identified a defect in fatty aldehyde dehydrogenase (FALDH), a component of the fatty alcohol:NAD oxidoreductase enzyme complex.^{3, 4, 5, 6, 7} The FALDH gene (renamed ALDH3A2) was subsequently cloned, and patients with SLS were found to have mutations in this gene. Enzymatic and genetic testing provide a reliable means for diagnosing SLS and determining carrier status. SLS is now the most widely recognized form of neuroichthyosis.

Pathophysiology

The primary genetic defect in SLS results in deficient activity of FALDH, which catalyzes the oxidation of fatty aldehyde to fatty acid. New insight into the pathogenesis of SLS is emerging from knowledge about the metabolic role of this enzyme. FALDH acts on fatty aldehydes derived from metabolism of fatty alcohol, phytanic acid (a branched-chain fatty acid), phytol (the alcohol precursor to phytanic acid), ether glycerolipids, and leukotriene B4. Tissue dysfunction is thought to be due to lipid storage in membranes. 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 SLS have deficient activity of FALDH and fatty alcohol:NAD oxidoreductase, which results in defective metabolism of both fatty aldehyde and fatty alcohol.

In SLS, FALDH deficiency impairs fatty alcohol oxidation and leads to accumulation of 16- and 18-carbon-long aliphatic alcohols. In cultured skin keratinocytes, elevated fatty alcohol is diverted into the synthesis of wax esters and alkyldiacylglycerol lipids. Accumulation of fatty alcohol and its lipid products in the intercellular membranes in the stratum corneum may cause disruption of the epidermal water barrier, which critically depends on its lipid composition. These lipid changes may cause the skin to dry out, resulting in ichthyosis.

Fatty alcohol and aldehyde may likewise alter the normal integrity of myelin membranes in the brain, leading to white-matter disease and spasticity. 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. Schiff-base aldehyde adducts with other amino-containing molecules, including key membrane enzymes and proteins, may also be detrimental to their function.

Patients with SLS accumulate leukotriene B4 and its omega-hydroxy degradation product, which are probably responsible for the pruritus seen in this disease. 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 SLS.

Frequency

United States

The incidence is not known.

International

The prevalence is estimated to be 0.4 cases per 100,000 people in Sweden.⁸ The prevalence elsewhere is not known.

Mortality/Morbidity

Patients with SLS usually survive well into adulthood. Life expectancy of those with SLS 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

SLS has been diagnosed in patients of all races. Most published cases of SLS involve whites.

Sex

SLS is autosomal recessive. Male and female individuals are equally affected.

Age

SLS is a genetic disease present from conception.

• Fetuses with SLS have histologic evidence of ichthyosis as early as the end of the second trimester.
• Most infants with SLS have cutaneous signs at birth; neurologic symptoms usually develop within 2 years.
• Symptoms persist throughout life.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Sjögren-Larsson syndrome (SLS) is a genetic disease evident before birth. Neonates are often born several weeks premature.

• Ichthyosis is usually the first symptom to prompt patients or parents to seek medical attention.
• • In most patients with SLS, the ichthyosis is apparent at birth. A collodion membrane (a parchmentlike membrane covering the skin) is not commonly present at birth but has been observed in about 15% of patients with this disorder.
  • About 30% of patients with SLS first develop ichthyosis after the neonatal period, usually during the first year of life; however, some patients do not have cutaneous disease until later in life.
  • In contrast to most other forms of ichthyosis, pruritus is a common complaint in SLS.
• Mental retardation develops during the first 2 years of life and is revealed by delays in achieving normal developmental milestones.
• Spastic diplegia or tetraplegia causes a delay in reaching motor milestones in infants with SLS.
• • Spasticity in the lower extremities often prevents patients from achieving independent ambulation.
  • Patients with SLS who can walk typically develop a spastic gait and require leg braces.
  • Patients with SLS are at risk for progressive leg contractures.
• Affected siblings may vary in the severity of neurologic symptoms.
• Speech is often delayed and is a complicating factor in judging the degree of mental retardation. Receptive language skills typically exceed those of expressive language.
• Seizures occur in about 40% of patients with SLS.
• Photophobia causes squinting in bright sunlight. Patients with decreased visual acuity may require corrective lenses.
• SLS is not neurodegenerative. Developmental skills, once gained, are usually maintained over time. However, if contractures progress, patients may loose the ability to ambulate.

Physical

• Ichthyosis is apparent upon physical examination in almost all patients with SLS.
• • The ichthyosis has a generalized distribution and is usually prominent on the trunk, extremities, flexures, axilla, nape of the neck, and back. The face is usually spared. The palms and soles are affected in 60% of patients with SLS.
  • Scales can be fine and dandrufflike, dark, or even platelike, especially on the shins and lower extremities. In some patients with SLS, hyperkeratosis with prominent skin markings is more obvious than scales.
  • Severity of the ichthyosis may not be apparent if the patient bathes shortly before examination (because bathing rehydrates the skin). As a consequence, the severity of the ichthyosis should be judged late in the day if the patient bathed in the morning. Likewise, the ichthyosis may not be evident immediately after the application of moisturizing lotions.
  • Excoriations due to pruritus often are present on patients with SLS.
• Spasticity is almost always present by age 2 years.
• • Spastic diplegia is much more common than spastic tetraplegia in individuals with this disorder. Contractures of the lower extremities often develop.
  • In infants with SLS, hypertonia is the most common neurologic finding on physical examination. Variable hypotonia occasionally precedes hypertonia. After infancy, hyperreflexia in the lower extremities is almost always present.
• Mental retardation varies from profound to mild; most patients with SLS have mild-to-moderate retardation, and rare patients have little cognitive impairment. In infants with SLS, retardation is revealed by developmental delay, which usually becomes evident during the first year of life.
• Speech problems beyond that expected from mental retardation alone are typically observed in individuals with SLS. These problems range from lack of speech to articulation disorders. Expressive speech is usually impaired more than receptive speech.
• The severity of the spasticity and the degree of mental retardation are correlated. However, severity of the ichthyosis is not related to the neurologic symptoms.
• Ophthalmologic findings include glistening white dots that affect the retina and retinal pigmentary changes.
• • Glistening white dots in a perifoveal distribution are present in at least 30% of patients with SLS. These dots may be pathognomonic for those with SLS, but they might not be apparent in young infants with the disorder.
  • Photophobia is common in individuals with SLS, and visual acuity is often decreased.
• In contrast to other disorders with ichthyosis, hair and nail abnormalities are not typical in individuals with SLS.
• Short stature is common owing to a combination of growth delay and leg contractures.
• Because the ichthyosis is usually present at birth and because neurologic symptoms appear later in the first 2 years of life, the differential diagnosis varies with age at presentation. During the neonatal period and early infancy, the differential diagnosis includes other forms of congenital ichthyosis, such as those listed in Differentials.

Causes

SLS is a genetic disease caused by mutations in the ALDH3A2 gene (previously known as ALDH10 and FALDH) located on subband 17p11.2. The mutations result in deficient activity of the FALDH enzyme and a severe reduction in the ability of FALDH to catalyze the oxidation of aliphatic aldehydes to their corresponding acids.

• SLS is inherited as an autosomal recessive trait. Two copies of the SLS gene, one from each parent, must be inherited for a patient to be affected with the disease. With the rare exception of the occurrence of a new mutation, each parent of a patient with SLS is a heterozygous carrier for an SLS gene.
• Like other autosomal recessive traits, most families have no history of SLS.
• The disease does not affect genetic carriers for SLS.
• For parents of a child affected with SLS, the recurrence risk for a subsequent pregnancy is 1 in 4, or 25%. This recurrence risk is independent of the number of children (affected or unaffected with SLS) the couple has had.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

During neonatal period and early infancy

Nonbullous congenital ichthyosiform erythroderma
Lamellar ichthyosis
X-linked ichthyosis (steroid sulfatase deficiency)

After neurologic symptoms have evolved

Infantile form of Gaucher disease (type II)
Multiple sulfatase deficiency
X-chromosome contiguous microdeletions of the steroid sulfatase gene and flanking genes
Neutral lipid storage disease (Dorfman-Chanarin syndrome)
Refsum disease
Other Sjögren-Larsson syndrome (SLS)-like disorders or pseudo-SLS (of unknown etiology)
Diagnosis of cerebral palsy with a secondary diagnosis of ichthyosis (This diagnosis was frequently applied before SLS was recognized.)

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• The definitive test for Sjögren-Larsson syndrome (SLS) is measurement of FALDH or fatty alcohol:NAD oxidoreductase in cultured skin fibroblasts.
• • Patients with SLS have activity less than 15% of the activity in individuals without SLS.
  • Heterozygous carriers for SLS typically have activity one half of the activity seen in individuals without any gene for SLS; however, some carriers overlap the lower end of the reference range.
  • The drawbacks to enzymatic testing of fibroblast cultures include the need for an invasive skin biopsy, requirement for a referral laboratory to grow the cells which typically requires 3-6 weeks, and the limited availability of diagnostic laboratories to perform the testing. However, skin fibroblasts afford a renewable source of patient material for biochemical testing and can be used as a source of DNA for mutation analysis.
• DNA tests can detect mutations in the ALDH3A2 gene and are a useful diagnostic alternative to enzymatic studies. However, this approach is complicated because more than 70 different mutations scattered throughout the gene have been found in patients with SLS.
• • A few mutations are commonly observed in patients from Europe, the Middle East and Brazil, but most mutations are specific for single families and require sequencing the entire gene to detect them, which is labor intensive and expensive.
  • After the mutations in a particular family are identified, targeted mutation screening is more convenient than enzyme studies for confirming the diagnosis of SLS in other affected family members; it also obviates the need for an invasive skin biopsy to grow fibroblast cultures for enzymatic testing.
  • Once the mutation is identified in a patient with SLS, DNA analysis is the most reliable test for detecting genetic carriers in the family.
  • DNA for mutation screening can be obtained from blood or noninvasively collected from a buccal swab or saliva specimen.
  • Using conventional methods for sequencing exons amplified from genomic DNA, at least 95% of the mutations that cause SLS can be identified. However, a few mutations can be missed, including certain splicing defects, duplications of one or more exons, and certain promoter or intronic mutations. In those instances, studies of RNA splicing and expression in cultured fibroblasts may be useful. 
• SLS 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.
• Other methods for diagnosing SLS, such as demonstration of elevated plasma fatty alcohols or urinary leukotriene B4 excretion, lack specificity and have not been adopted for routine clinical use. 
• The usual metabolic screening tests (eg, serum amino acids, urine organic acids, urine metabolic screens) are of no diagnostic value.
• Routine blood tests (eg, for electrolytes, transaminases, renal function, CBC count) reveal results within reference ranges.

Imaging Studies

• Brain MRI is useful for detecting white-matter disease, which is observed in most patients with SLS.
• • The myelin abnormality usually involves the periventricular regions, the centrum semiovale, the corpus callosum, and frontal and parietal lobes.
  • In infants with SLS, initial MRI findings may appear normal, with evidence of white-matter disease emerging later, as the patient ages.
• Proton magnetic resonance spectroscopy of the brain often reveals an unidentified peak in the lipid region of the spectrum. The specificity of this lipid peak in those with SLS is yet to be determined.

Other Tests

• Electrophysiologic studies help define the extent of neurologic disease.
• Somatosensory-evoked potentials and brainstem auditory-evoked potentials are outside the reference ranges in some patients with SLS, but nerve conduction velocities are typically within the reference range.

Procedures

• Skin biopsy is frequently performed in patients with SLS to examine the histopathology of the skin; this is useful for diagnosing certain forms of ichthyosis.
• Skin biopsy should be performed to establish fibroblast cultures for enzymatic testing.

Histologic Findings

• A skin biopsy examined under light microscopy typically shows hyperkeratosis, papillomatosis, and a somewhat thickened granular layer.
• Ultrastructural analysis reveals abnormal lipid inclusions in the cytoplasm of the granular cells and in the stratum corneum, and defective lamellar bodies in the granular keratinocytes.
• However, these histologic changes are not diagnostic for SLS because they are observed in other forms of ichthyosis.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Cutaneous symptoms of Sjögren-Larsson syndrome (SLS) require constant attention. For this reason, parents and caregivers often perceive the ichthyosis as the most obvious and time-consuming symptom of SLS.
• • The mainstay of therapy for ichthyosis consists of applying topical moisturizing creams and keratolytic agents, such as alpha-hydroxyacid (eg, lactic acid, glycolic acid), salicylic acid, and urea.
  • Daily water baths help keep the skin hydrated.
  • 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). Retinoids are usually stored in the body for long periods because of their fat-soluble properties. Newer, short-lived retinoids (eg, acitretin) may circumvent some of the problems associated with tissue storage of the drug; however, experience with these drugs in patients with SLS is limited.
• Seizures, if recurrent, usually respond to standard anticonvulsant medications.
• Experience in treating the spasticity in individuals with SLS with baclofen (Lioresal) is not encouraging. Botulinum toxin (Botox®) injections have been used in several patients with SLS; however, anecdotal results indicate only a limited favorable response.

Surgical Care

• Spasticity in patients with SLS is often improved by surgical procedures (eg, tendon lengthening, adductor release, dorsal root rhizotomy).
• These procedures may help some patients with SLS become ambulatory.

Consultations

Experience indicates that most patients have received consultative attention from multiple subspecialists before SLS is initially diagnosed. After SLS is diagnosed, continue subspecialty care to promote an optimal outcome.

• Consultation with a dermatologist is important in treating the ichthyosis. Most patients with SLS respond to topical keratolytic agents and moisturizing creams. Systemic retinoids are effective in treating the ichthyosis.
• A child neurologist should take an active role in evaluating and managing neurologic symptoms in all patients with SLS. This is particularly important for recommendations concerning drug or surgical intervention for spasticity and anticonvulsant therapy for seizure disorder.
• Patients with SLS typically benefit from regular physical therapy to maintain ambulation and to prevent contractures from progressing.
• Some patients with this disorder may require consultation with a surgeon to treat spasticity and contractures.

Diet

• Dietary supplementation with medium-chain triglycerides reportedly helped the ichthyosis in several patients with SLS; however, results have been inconsistent.
• No convincing evidence suggests that changes in diet reduce neurologic symptoms.

Activity

• Physical activity, particularly ambulation, is impaired in most patients with SLS.
• Including physical therapy in the care of patients with SLS is important to prevent or mitigate leg contractures that naturally develop in this disease.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Drug Category: Retinoids

These drugs are used to treat ichthyosis in patients with SLS; however, the US Food and Drug Administration (FDA) has not specifically approved retinoids for this indication. Ichthyosis has historically responded to systemic etretinate, but this long-used retinoid is no longer available. Acitretin (Soriatane) has been used off label to treat various forms of ichthyosis, but the drug is FDA approved only for the treatment of severe psoriasis in adults. The safety and efficacy of acitretin in children with Sjögren-Larsson syndrome (SLS) is not established. The prescribing physician should contact Roche Pharmaceuticals for the latest information before administering acitretin.

Drug Category: Leukotriene inhibitors

Inhibitors of leukotriene B4 synthesis (eg, zileuton) lower levels of this inflammatory mediator in SLS. Anecdotal experience and a small clinical trial in 5 patients with SLS suggest that zileuton therapy improves pruritus in some patients.⁹ Zileuton is currently FDA approved for use in asthma. It is not approved for use in SLS or in children and, therefore, must be prescribed off label.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Patients with Sjögren-Larsson syndrome (SLS) may require inpatient care for brain MRI or ophthalmologic examination under general anesthesia or for acute treatment and management of seizures.

Further Outpatient Care

• The initial evaluation and workup for SLS can usually be performed on an outpatient basis.

In/Out Patient Meds

• Topical moisturizing lotions, keratolytic agents, anticonvulsants (if necessary), and retinoids can be administered as outpatient medications.

Transfer

• Patients with SLS might need to be transferred to another medical facility if specialty expertise is not otherwise available.

Deterrence/Prevention

• Because SLS is inherited in an autosomal recessive manner and because most families do not have a history of the disease, preventing the first occurrence of SLS in a family is not possible.
• Genetic counseling and prenatal diagnosis can prevent the birth of a subsequent child with SLS.
• • After SLS is diagnosed in a family, offer genetic counseling to provide the family information about the risk of recurrence.
  • Prenatal diagnosis can be accomplished by measuring FALDH enzyme activity in cultured chorionic villi cells obtained at 8.5-11 weeks' gestation or in cultured amniocytes obtained at about 16 weeks' gestation. Many parents elect to terminate a pregnancy when a fetus has SLS.
  • DNA-based prenatal diagnosis can be performed by using fetal-derived DNA if the mutations are identified in the family with SLS.

Complications

• Contractures are more likely to develop in the lower extremities than in the upper extremities.
• Seizure disorder may occur.

Prognosis

The prognosis for any patient with SLS ultimately depends on the severity of the neurologic disease.

• The clinical course of SLS cannot be predicted in early infancy before neurologic symptoms have matured.
• SLS is not neurodegenerative. Most patients with the disease do not get clinically worse over time.
• With adequate medical therapy, most patients with SLS survive into adulthood.

Patient Education

• Parents and caregivers of individuals with SLS, as well as patients with SLS, need education about the daily management of the ichthyosis.
• Training to provide home-based physical therapy is useful to prevent contractures.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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17. van den Brink DM, van Miert JN, Dacremont G, et al. Identification of fatty aldehyde dehydrogenase in the breakdown of phytol to phytanic acid. Mol Genet Metab. May 2004;82(1):33-7. [Medline].
18. van Domburg PH, Willemsen MA, Rotteveel JJ, et al. Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH- deficient patients. Neurology. Apr 22 1999;52(7):1345-52. [Medline].
19. Willemsen MA, Cruysberg JR, Rotteveel JJ, et al. Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjogren-Larsson syndrome. Am J Ophthalmol. Dec 2000;130(6):782-9. [Medline].
20. Willemsen MA, IjLst L, Steijlen PM, et al. Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren-Larsson syndrome. Brain. 2001;124:1426-1437.
21. Willemsen MA, Rotteveel JJ, de Jong JG, et al. Defective metabolism of leukotriene B4 in the Sjogren-Larsson syndrome. J Neurol Sci. Jan 15 2001;183(1):61-7. [Medline].
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Article Last Updated: May 9, 2008