AUTHOR INFORMATION

Section 1 of 10

Authored by William B Rizzo, MD, Professor, Department of Pediatrics, University of Nebraska Medical Center

William B Rizzo, MD, is a member of the following medical societies: American Society of Human Genetics, and Society for Inherited Metabolic Disorders

Edited by Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	William B Rizzo, MD
Editor's Email:	Erawati V Bawle, MD, FAAP, FACMG

eMedicine Journal, May 3 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 10

Background: In 1957, Sjögren and Larsson described a cohort of Swedish patients with an unusual combination of symptoms consisting of congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. 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.

In 1988, 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. The FALDH gene recently was 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), 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.

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

Fatty alcohol may likewise alter the normal integrity of myelin membranes in the brain, leading to white-matter disease and spasticity. In addition, fatty aldehydes, which are reactive molecules, can form covalent Schiff-base derivatives with phosphatidylethanolamine, which may influence 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 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:

• In the US: The incidence is not known.

• Internationally: The prevalence is estimated to be 0.4 case per 100,000 people in Sweden. 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 nonprogressive 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 Caucasians.

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

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 10

History: SLS is a genetic disease evident before birth. Neonates are often born several weeks prematurely.

• 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 parchment-like membrane covering the skin) is not commonly present at birth, but it 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, but 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 in SLS and is revealed by delays in achieving normal developmental milestones.



• Spastic diplegia or tetraplegia causes a delay in reaching motor milestones and is a complicating factor in judging the degree of mental retardation 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.
  
  
  
• Speech is often delayed. 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 on 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 dandruff-like, 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, it is important to judge the severity of the ichthyosis 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 almost always is present by the time the individual is aged 2 years.


• • Spastic diplegia is 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, but most patients with SLS have mild-to-moderate retardation. 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 affecting 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, 1 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 10

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 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 10

Lab Studies:

• The definitive test for 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.
  
  
  
• DNA diagnostic tests to detect mutations in the FALDH gene now are possible. However, this approach is complicated because more than 70 different mutations scattered throughout the gene have been found in patients with SLS.


• • A few of these mutations are commonly observed in patients of European and Middle Eastern descent, 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 mutation in a particular family is known, targeted mutation screening is more direct than enzyme studies and does not require skin biopsy to grow fibroblast cultures.
  
  
  
  • Mutation analysis is the most reliable test for identifying genetic carriers.
  
  
  
• SLS also can be diagnosed by directly demonstrating defective fatty alcohol oxidation in a skin-biopsy sample by using a histochemical staining method. This approach is not quantitative.



• 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) 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 MRIs 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.

TREATMENT

Section 6 of 10

Medical Care:

• Cutaneous symptoms of 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 often is 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 10

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 SLS is not established. The prescribing physician should contact Roche Pharmaceuticals for the latest information before administering acitretin.

Drug Name	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.
Adult Dose	25-50 mg/d PO as a single dose with main meal
Pediatric Dose	Not established; limited data suggest 0.3-0.5 mg/kg/d PO
Contraindications	Documented hypersensitivity; severely obese; pregnancy or contemplated pregnancy; long-term use in children; concomitant use of vitamin A preparations
Interactions	Increases toxicity methotrexate (avoid concomitant use); interferes with effects of microdosed progestin minipill; coadministration with alcohol may enhance synthesis of etretinate, which has longer half-life (>120 d)
Pregnancy	X - Contraindicated in pregnancy
Precautions	Women of childbearing age must be able to comply with effective contraception; recommended that contraception be continued for at least 3 y after stopping treatment; etretinate may form and takes about 2-3 y to clear from body; test aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lipotropic hormone (LPH) tests before therapy, at 1- to 2-wk intervals until stable, and then at intervals as clinically indicated

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 (Willemsen, 2001). 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.

Drug Name	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.
Adult Dose	600 mg PO qid
Pediatric Dose	Not established, limited data in patients with SLS (age 14-21 y) suggest 400 mg PO tid or 600 mg PO qid
Contraindications	Documented hypersensitivity; active liver disease or transaminase elevation >3 times the upper limit of normal
Interactions	Coadministration with theophylline decreases theophylline clearance; interferes with warfarin clearance and increases in activated partial thromboplastin time; increases propanolol and terfenadine levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in liver disease; may increase levels of liver enzymes; of 2458 patients with asthma, 4.6% had ALT level > 3 times above upper limit of normal range; in some, ALT level decreased to normal with continued therapy; measure serum liver transaminase (eg, ALT) levels before therapy and monthly for first few months; discontinue if serum ALT level persistently elevated

FOLLOW-UP

Section 8 of 10

Further Inpatient Care:

• Patients with 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 of gestation or in cultured amniocytes obtained at about 16 weeks of 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 a member of 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.

TEST QUESTIONS

Section 9 of 10

CME Question 1: Which symptom is not seen in Sjögren-Larsson syndrome (SLS)?

A: Seizures
B: Ichthyosis
C: Spastic diplegia
D: Deafness
E: Mental retardation

The correct answer is D: SLS does not affect hearing. Symptoms consist of congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia.

CME Question 2: What is the best diagnostic test for suspected Sjögren-Larsson syndrome (SLS)?

A: Skin biopsy with histologic examination to evaluate hyperkeratosis, papillomatosis, and a thin granular layer
B: Measurement of fatty aldehyde dehydrogenase (FALDH) activity in cultured skin fibroblasts
C: Brain MRI to assess white-matter disease
D: Urine metabolic screening
E: Brain magnetic resonance spectroscopy to search for a lipid peak

The correct answer is B: Demonstration of deficient enzyme activity is the definitive test for SLS. Demonstration of mutations in the fatty aldehyde dehydrogenase gene (ALDH3A2 gene) is an acceptable option.

Pearl Question 1 (T/F): Sjögren-Larsson syndrome (SLS) is an inherited disorder.

The correct answer is True: SLS is inherited in an autosomal recessive fashion. Both parents are heterozygous carriers for the SLS gene.

Pearl Question 2 (T/F): Parents of a patient with Sjögren-Larsson syndrome (SLS) cannot know their risk of having another child with SLS.

The correct answer is False: For parents of a child affected with SLS, the recurrence risk for a subsequent pregnancy is 1 in 4, or 25%. Prenatal diagnosis of SLS can be accomplished by measuring FALDH enzyme activity in cultured chorionic villi cells obtained at 8.5-11 weeks of gestation or in cultured amniocytes obtained at about 16 weeks of gestation. Many parents elect to terminate a pregnancy when a fetus has SLS.

Pearl Question 3 (T/F): Ophthalmologic findings in individuals with Sjögren-Larsson syndrome (SLS) are usually normal.

The correct answer is False: Glistening, white dots affecting the retina with a perifoveal distribution and retinal pigmentary changes are often observed in patients with SLS. Photophobia is a common complaint. Many patients develop poor vision.

Pearl Question 4 (T/F): An infant develops ichthyosis when aged 6 months. Physical examination reveals hypertonia. Because the ichthyosis was not present at birth, the diagnosis of Sjögren-Larsson syndrome (SLS) should be eliminated.

The correct answer is False: Some patients with SLS initially develop ichthyosis after the neonatal period.

BIBLIOGRAPHY

Section 10 of 10

• De Laurenzi V, Rogers GR, Hamrock DJ, et al: Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet 1996 Jan; 12(1): 52-7[Medline].
• Jagell S, Gustavson KH, Holmgren G: Sjogren-Larsson syndrome in Sweden. A clinical, genetic and epidemiological study. Clin Genet 1981 Apr; 19(4): 233-56[Medline].
• Rizzo WB, Craft DA: Sjogren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest 1991 Nov; 88(5): 1643-8[Medline].
• Rizzo WB, Carney G: Sjogren-Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mutat 2005; 26: 1-10.
• Rizzo WB: Sjogren-Larsson syndrome: fatty aldehyde dehydrogenase deficiency. In: The Metabolic and Molecular Bases of Inherited Disease. 8th ed. Vol 2. New York: McGraw-Hill Professional; 2001: 2239-58.
• Sjogren T, Larsson T: Oligophrenia in combination with congenital ichthyosis and spastic disorders. Acta Psychiatr Neurol Scand 1957; 32: 1-113.
• van Domburg PH, Willemsen MA, Rotteveel JJ, et al: Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH- deficient patients. Neurology 1999 Apr 22; 52(7): 1345-52[Medline].
• Willemsen MA, Lutt MA, Steijlen PM, et al: Clinical and biochemical effects of zileuton in patients with the Sjogren-Larsson syndrome. Eur J Pediatr 2001 Dec; 160(12): 711-7[Medline].

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