Genetics of Sjogren-Larsson Syndrome

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.

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.

Sjögren-Larsson syndrome (SLS) is a genetic disease evident before birth. Neonates are often born several weeks premature.[27]

Ichthyosis is usually the first symptom to prompt patients or parents to seek medical attention.[28] In most patients with Sjögren-Larsson syndrome, 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 Sjögren-Larsson syndrome 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 Sjögren-Larsson syndrome.

Intellectual disability 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 Sjögren-Larsson syndrome. Spasticity in the lower extremities often prevents patients from achieving independent ambulation. Patients with Sjögren-Larsson syndrome who can walk typically develop a spastic gait and require leg braces. Patients with Sjögren-Larsson syndrome 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 intellectual disability. Receptive language skills typically exceed those of expressive language.

Seizures occur in about 40% of patients with Sjögren-Larsson syndrome.

Photophobia causes squinting in bright sunlight. Patients with decreased visual acuity may require corrective lenses.

Sjögren-Larsson syndrome is not neurodegenerative. Developmental skills, once gained, are usually maintained over time. However, if contractures progress, patients may loose the ability to ambulate.

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. The face is usually spared. The palms and soles are affected in 60% of patients with Sjögren-Larsson syndrome. Scales can be fine and dandrufflike, dark, or even platelike, especially on the shins and lower extremities. In some patients with Sjögren-Larsson syndrome, 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 are often present on patients with Sjögren-Larsson syndrome.

Spasticity is almost always present by age 2 years.[10] Spastic diplegia is much more common than spastic tetraplegia in individuals with this disorder. Contractures of the lower extremities often develop. In infants with Sjögren-Larsson syndrome, 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.

Considerable variation may be seen in the motor abilities of affected siblings.[29]

Intellectual disability varies from profound to mild; in most patients with Sjögren-Larsson syndrome, however, it is mild to moderate, and rare patients have little cognitive impairment.[7] In infants with Sjögren-Larsson syndrome, intellectual disability is revealed by developmental delay, which usually becomes evident during the first year of life.

Speech problems beyond that expected from intellectual disability alone are typically observed in individuals with Sjögren-Larsson syndrome.[30] Pseudobulbar dysarthria is most common. Expressive speech is usually impaired more than receptive speech.

The severity of the spasticity and the degree of intellectual disability 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.[11] Glistening white dots in a perifoveal distribution are present in most patients with Sjögren-Larsson syndrome. These dots may be pathognomonic for those with Sjögren-Larsson syndrome, but they might not be apparent in young infants with the disorder. Photophobia is common in individuals with Sjögren-Larsson syndrome, and visual acuity is often decreased.

In contrast to other disorders with ichthyosis, hair and nail abnormalities are not seen in individuals with Sjögren-Larsson syndrome.

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.

Sjögren-Larsson syndrome is a genetic disease caused by mutations in the ALDH3A2 gene (previously known as ALDH10 and FALDH) located on subband 17p11.2.[6, 31] 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.

Sjögren-Larsson syndrome 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 Sjögren-Larsson syndrome is a heterozygous carrier for an SLS gene.

Like other autosomal recessive traits, most families have no history of Sjögren-Larsson syndrome. The disease does not affect genetic carriers for Sjögren-Larsson syndrome. For parents of a child affected with Sjögren-Larsson syndrome, 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 Sjögren-Larsson syndrome) the couple has had.

The definitive test for Sjögren-Larsson syndrome (SLS) 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. Heterozygous carriers for Sjögren-Larsson syndrome typically have one half of the activity seen in individuals without any gene for the syndrome; 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 considered a diagnostic test of choice.[6] A few mutations are commonly observed in patients from Europe, the Middle East and Brazil, but most mutations are specific for single families and may require sequencing the entire gene to detect them.

After the mutations in a particular family are identified, targeted mutation screening is more convenient than enzyme studies for confirming the diagnosis of Sjögren-Larsson syndrome 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 Sjögren-Larsson syndrome, 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.

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. Other methods for diagnosing Sjögren-Larsson syndrome, 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.

Brain MRI is useful for detecting white-matter disease, which is observed in most patients with Sjögren-Larsson syndrome.[12] The myelin abnormality usually involves the periventricular regions, the centrum semiovale, the corpus callosum, and frontal and parietal lobes. In infants with Sjögren-Larsson syndrome, 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 Sjögren-Larsson syndrome is yet to be determined.

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 Sjögren-Larsson syndrome, but nerve conduction velocities are typically within the reference range.[32]

Optical coherence tomography is useful procedure to detect early evidence of cystoid foveal degeneration associated with Muller cell degeneration in the retina of patients.[33]

Skin biopsy is frequently performed in patients with Sjögren-Larsson syndrome 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.

A skin biopsy examined under light microscopy typically shows hyperkeratosis, papillomatosis, and a somewhat thickened granular layer. However, these histologic changes are not diagnostic for Sjögren-Larsson syndrome because they are observed in other forms of ichthyosis.

Ultrastructural analysis of the skin reveals abnormal lipid inclusions in the cytoplasm of the granular cells and in the stratum corneum, and defective lamellar bodies in the granular keratinocytes.[34, 23] The intercellular membranes of the stratum corneum are depleted and show nonlamellar lipid inclusions. Lamellar bodies are not secreted properly and become entombed in the corneocytes of the stratum corneum.

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 Sjögren-Larsson syndrome. 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.[35] 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 Sjögren-Larsson syndrome is limited.[35, 36]

Patients with severe pruritus may benefit from treatment with zileuton, which blocks leukotriene B4 synthesis.[13] Seizures, if recurrent, usually respond to standard anticonvulsant medications.

Experience in treating the spasticity in individuals with Sjögren-Larsson syndrome with baclofen (Lioresal) is not encouraging. Botulinum toxin (Botox®) injections have been used in several patients with Sjögren-Larsson syndrome; however, anecdotal results indicate only a limited favorable response.

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 Sjögren-Larsson syndrome become ambulatory.

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

Consultation with a dermatologist is important in treating the ichthyosis. Most patients with Sjögren-Larsson syndrome 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 Sjögren-Larsson syndrome. This is particularly important for recommendations concerning drug or surgical intervention for spasticity and anticonvulsant therapy for seizure disorder.

Patients with Sjögren-Larsson syndrome 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.

Dietary supplementation with medium-chain triglycerides reportedly helped the ichthyosis in several patients with Sjögren-Larsson syndrome; however, results have been inconsistent.[7]

No convincing evidence suggests that changes in diet reduce neurologic symptoms.

Physical activity, particularly ambulation, is impaired in most patients with Sjögren-Larsson syndrome. 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.

Class Summary

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.

Acitretin (Soriatane)

Metabolite of etretinate and related to retinoic acid and retinol (vitamin A). Mechanism of action unknown, but thought to exert therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells. Consider only in patients with severe ichthyosis that does not respond adequately to safer topical agents, such as keratolytic agents and moisturizing lotions.

Class Summary

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.[13] 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.

Zileuton (Zyflo)

Inhibits leukotriene formation, which decreases neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, capillary permeability, and smooth muscle contractions. Consider use in patients with agonizing pruritus or severe excoriations. Not all patients respond; those who do usually improve during first week of therapy.

The initial evaluation and workup for Sjögren-Larsson syndrome can usually be performed on an outpatient basis.

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.

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

Patients with Sjögren-Larsson syndrome might need to be transferred to another medical facility if specialty expertise is not otherwise available.

Because Sjögren-Larsson syndrome is inherited in an autosomal recessive manner and because most families do not have a history of the disease, preventing the first occurrence of Sjögren-Larsson syndrome in a family is not possible.

Genetic counseling and prenatal diagnosis can prevent the birth of a subsequent child with Sjögren-Larsson syndrome. After Sjögren-Larsson syndrome 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 Sjögren-Larsson syndrome.

DNA-based prenatal diagnosis can be performed by using fetal-derived DNA if the mutations are identified in the family with Sjögren-Larsson syndrome.

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

The prognosis for any patient with Sjögren-Larsson syndrome ultimately depends on the severity of the neurologic disease. The clinical course of Sjögren-Larsson syndrome cannot be predicted in early infancy before neurologic symptoms have matured. Sjögren-Larsson syndrome is not neurodegenerative. Most patients with the disease do not get clinically worse over time. With adequate medical therapy, most patients with Sjögren-Larsson syndrome survive into adulthood.

Parents and caregivers of individuals with Sjögren-Larsson syndrome, as well as patients with Sjögren-Larsson syndrome, need education about the daily management of the ichthyosis.

Training to provide home-based physical therapy is useful to prevent contractures.