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Sjögren-Larsson syndrome

Sjögren-Larsson syndrome
Author:
Amy T Waldman, MD
Section Editors:
Francisco González-Scarano, MD
Marc C Patterson, MD, FRACP
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last updated: Oct 27, 2021.

INTRODUCTION — Sjögren-Larsson syndrome (SLS; MIM #270200) is an autosomal recessive neurocutaneous disorder caused by an inborn error of metabolism involving fatty alcohol oxidation. The disorder was first described in 1957 by Sjögren and Larsson, who reported a series of 28 patients with a clinical triad of ichthyosis, spastic diplegia or quadriplegia, and intellectual disability (mental retardation, oligophrenia) [1].

This topic will review the pathogenesis, clinical features, diagnosis, and management of SLS.

PATHOGENESIS — SLS is a disorder of fatty alcohol metabolism (figure 1) caused by a deficiency of the enzyme fatty aldehyde dehydrogenase (FALDH), a component of the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex [2,3].

FAO is composed of two distinct proteins that sequentially catalyze the oxidation of fatty alcohols to fatty aldehydes and then to fatty acids (figure 2) [2,3]:

Fatty alcohol dehydrogenase (FADH), which catalyzes the oxidation of medium- and long-chain fatty alcohols to fatty aldehydes

FALDH, which catalyzes the oxidation of fatty aldehydes to fatty acids

Lipid accumulation is the probable mechanism of cutaneous and neurologic disease in SLS [4,5]. Fatty alcohols accumulate in the skin, disrupting the epidermal water barrier, and resulting in transepidermal water loss and ichthyosis [3]. Experimental evidence supports a permeability barrier abnormality in the stratum corneum of skin [6]. Despite their disrupted oxidation, the plasma concentration of fatty alcohols is not elevated in all patients with SLS [7].

Although the precise mechanism of neurologic disease in SLS is uncertain, the deficiency of fatty alcohol oxidation may impair the structural and/or functional integrity of myelin membranes in the central nervous system, thereby leading to the neurologic features, including leukoencephalopathy [5].

In SLS, myelination is delayed, and some patients have unmyelinated subcortical association fibers, suggesting that the process of myelination does not reach completion in these patients [8,9]. Myelin deficiency (retarded myelination and/or dysmyelination) may involve the brainstem (corticospinal tracts) and, in severe cases, the corpus callosum [4,8]. The cerebellum and cerebral gray matter are spared [8].

The deficiency of FALDH also affects the metabolism of leukotriene B4 (LTB4), a proinflammatory mediator. Normally, LTB4 is inactivated by sequential oxidation, first to omega-hydroxy-LTB4, then to omega-aldehyde-LTB4, and lastly, in a step catalyzed by FALDH, to omega-carboxy-LTB4 [7,10]. Other pathways cannot compensate for the FALDH deficiency in patients with SLS [11], leading to accumulation of LTB4 and omega-hydroxy-LTB4. These products are probably responsible for the severe pruritus that is characteristic of the disease. However, it is unclear if the defective degradation of LTB4 contributes to the neurologic involvement in SLS [7].

Genetics — SLS is caused by pathogenic variants in the ALDH3A2 gene on chromosome 17p11.2 [12]. More than 105 pathogenic variants in the ALDH3A2 gene can lead to the phenotype of SLS; variant types include missense, frame shift, splice site, in-frame insertions/deletions, nonsense, and large rearrangements [13-15]. While most variants are private, common pathogenic variants associated with founder effects have been identified [14,16].

EPIDEMIOLOGY — In Vasterbotten county, Sweden, where Sjögren and Larsson identified this syndrome, the prevalence of SLS was 8.3 per 100,000, perhaps due to inbreeding, whereas the overall prevalence in Sweden was 0.4 per 100,000 [17]. Although SLS occurs worldwide in various ethnic groups, the prevalence and incidence outside of Sweden are unknown [18].

CLINICAL FEATURES — SLS is associated with the following characteristic clinical features [1,4,19,20]:

Ichthyosis and pruritus

Spastic diplegia or quadriplegia

Intellectual disability (mental retardation)

Ocular abnormalities: photophobia, macular degeneration with retinal crystals, and decreased visual acuity

Leukoencephalopathy

The neurologic manifestations of SLS superficially resemble those of cerebral palsy [21,22]. Most of the clinical symptoms of SLS are apparent in the first years of life, after which they persist with little or no change [8,19,21]. In older children and adults, there is no apparent correlation of disease severity with age [21]. In addition, the severity of the cutaneous symptoms does not correlate with severity of the neurologic manifestations [20].

Even within individual families affected by SLS, there is phenotypic heterogeneity. Some children have a mild form of SLS, with less severe dermatologic and neurologic difficulties [4].

Cutaneous — The dermatologic features are typically the earliest presenting symptoms, beginning with skin erythema at birth. In the latter half of the first year of life, the skin becomes dry, rough, and scaly, due to a defect in keratinization, and it has a brown-yellow discoloration. The flexor surfaces of the extremities, neck, axilla, and umbilicus are predominantly affected, while the face is usually spared.

Severe pruritus is nearly universal in SLS and distinguishes SLS from other ichthyoses [22].

A collodion membrane at birth ("collodion baby") is unusual in SLS, whereas it is characteristic of lamellar ichthyosis and congenital ichthyosiform erythroderma. (See 'Differential diagnosis' below.)

Motor — Children with SLS usually develop pyramidal signs in the first two years of life. The legs are usually more severely affected than the arms [4]. Despite the insidious onset of the spasticity, children with SLS may nevertheless learn to walk. However, most become wheelchair dependent during late childhood or early adolescence, and joint contractures frequently develop in the legs [19]. Generalized dystonia was reported in one child with SLS [23].

Cognitive — Developmental delay is usually apparent during the first year of life, and most patients with SLS have mild to moderate intellectual disability (mental retardation) [19]. However, a minority have normal intelligence [5].

Speech and language — Speech and language problems in SLS are related to both motor and cognitive impairments. In one series, children severely affected with SLS could speak only in short sentences and often produced incomprehensible syllables due to pseudobulbar dysarthria, whereas language comprehension was relatively spared [4].

Ocular — Retinal crystals, which appear as foveal and perifoveal glistening white dots, are present in all patients with SLS beginning in early childhood [4,24,25]. Younger patients are often difficult to examine due to poor cooperation related to photophobia during the funduscopic examination; this problem may explain the absence of reports of retinal crystals in children younger than two to four years of age [4,26].

Decreased visual acuity is common in SLS, and in some patients may be due to dysmyelination of the optic tracts [4].

Additional — The affected children are often born prematurely. It is hypothesized that premature birth (at a median of 36 weeks, interquartile range 34 to 37 weeks) occurs due to elevated leukotriene B4 (LTB4) in amniotic fluid from urinary excretion by the affected fetus [27]. The frequency of seizures in patients with SLS ranges from 0 to 40 percent [4,5,20]. Growth delay and contractures may lead to short stature [18,20].

Neuroimaging — In patients with SLS, brain magnetic resonance imaging (MRI) shows delayed myelination (image 1) with high signal on T2-weighted imaging in the periventricular white matter with either frontal (image 2) or parieto-occipital (image 3) predominance [8]. The same areas appear normal or mildly hypointense on T1-weighted images. The severity of white matter abnormalities on MRI does not correlate with the age of the patient or the symptomatology [8].

In some patients, magnetic resonance spectroscopy (MRS) shows a high abnormal lipid peak measuring 1.3 parts per million in the periventricular white matter, especially around the frontal and posterior trigones, with a greater prominence in the latter (image 4) [8]. The lipid peak suggests local accumulation of the unusual free lipids or lipophilic substances, such as long-chain fatty alcohols. In one study, two patients had this abnormality on MRS before white matter abnormalities were detectable on conventional MRI [4]. The intensity of the white matter lipid peak at 1.3 parts per million may be inversely correlated with age in adults with SLS, leading to speculation that an unknown compensatory mechanism leads to reduced lipid accumulation and disease severity over time [21].

In the cerebral white matter, MRS shows another, smaller peak at 0.8 to 0.9 ppm. The peaks at 0.8 to 0.9 and 1.3 ppm reflect the methyl (CH3) and methylene (CH2) groups on separate lipid molecules. In addition, creatine, choline, and myoinositol were elevated in cerebral white matter, while N-acetylaspartate and glutamate were normal. These findings on MRS suggest that SLS leads to gliosis without significant axonal loss [8].

Pathology — The key findings in SLS are gliosis and absence of myelin. Multiple features reflecting abnormal myelin structure have been reported. The cerebral white matter, cerebellar white matter, and pyramidal tracts have a decreased number of myelinated nerve fibers. One autopsy report revealed a reduction of in the number of axons in the retina and optic nerve, as well as a loss of neurons in the lateral geniculate bodies [28]. While some axonal loss occurs, gliosis is more striking. Gross sections of brain reveal diffuse cerebral atrophy with gliosis.

Microscopically, lipoid deposits are found in multiple regions, including subpial, subependymal, and perivascular glial layers; subpial and perivascular spaces; cerebral white matter; and the brainstem. Perivascular macrophages contain lipofuscin-like pigments in the cytoplasm that probably represent the breakdown products of the lipoid substances. Similarly, ellipsoid bodies, found in the white matter, subpial, and periventricular glial layers, may reflect degraded products of the astrocytic processes as well [29]. Finally, spheroid bodies, representing axonal injury, have been reported in the relay nuclei, reticular formation, and periventricular gray matter of the fourth ventricle [29]. Examination of the retina showed retinal thinning, cystic macular degeneration, retinal pigment epithelium atrophy, and deficiency of macular pigment [30].

DIAGNOSIS — The genetic diagnosis of SLS can be confirmed by sequence analysis of the ALDH3A2 gene that encodes FALDH [12,31,32]. Alternatively, the diagnosis of SLS can be confirmed by demonstrating fatty aldehyde dehydrogenase (FALDH) deficiency in cultured skin fibroblasts or leukocytes. In patients with SLS, the activity of FALDH is reduced to <15 percent of normal [2,3].

The diagnosis of SLS should be suspected in infants and children with both ichthyosis and neurologic symptoms [5]. Detection of macular crystalline inclusions in patients with two of the other major clinical features of SLS (ichthyosis, spasticity, or intellectual disability) is pathognomonic for this disease [30]. The diagnosis may be delayed or missed in the neonatal period and early infancy, a time when the cutaneous manifestations are typically mild [19], and the neurologic signs and symptoms are usually occult. However, suspicion for the diagnosis of SLS should be raised in any infant with congenital ichthyosis, particularly when the ichthyosis has the characteristic brownish-yellow discoloration and wrinkled hyperkeratosis observed in SLS.

The preferred method for prenatal diagnosis involves amniocentesis or chorionic villus sampling; the prenatal diagnosis can be made by demonstrating deficient fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) and FALDH activity in amniocytes and cultured chorionic villi cells [33,34]. The prenatal diagnosis of SLS was first demonstrated by fetal skin biopsy at 23 weeks gestation [33], but the diagnosis can be missed if the analysis is performed earlier in the pregnancy.

DIFFERENTIAL DIAGNOSIS — The typical presenting symptoms of SLS in newborns and early infancy are dermatologic, and the differential diagnosis includes the primary ichthyoses. Once neurologic symptoms have developed, neuroichthyotic disorders must be considered [18].

Primary ichthyoses — The ichthyoses are a heterogeneous group of dermatoses caused by abnormal keratinization with variable modes of inheritance. Ichthyosis may be a primary disorder, in which the skin is predominantly or solely affected, or a component of a multisystem disorder. The dermatologic features of SLS may resemble those of several primary ichthyoses:

Ichthyosis vulgaris (MIM #146700)

X-linked ichthyosis (MIM #308100)

Lamellar ichthyosis (MIM #242300)

Congenital ichthyosiform erythroderma (MIM #242100)

Epidermolytic hyperkeratosis (MIM #113800)

These disorders are discussed in detail separately. (See "The genodermatoses: An overview", section on 'Disorders of keratinization'.)

Neurocutaneous disorders — As in SLS, ichthyosis may also be seen in other systemic, metabolic, and neurologic diseases. Although data are limited, anecdotal observations indicate that only about one-half of patients with cutaneous and neurologic features of SLS turn out to have fatty aldehyde dehydrogenase (FALDH) deficiency [5].

Pseudo-SLS is a term sometimes applied to an SLS-like disorder when the etiology cannot be established [18].

Refsum disease (MIM #266500) is an autosomal recessive disorder associated with the accumulation of phytanic acid in plasma and tissues. The skin manifestations are typically mild, resembling ichthyosis vulgaris. Other symptoms include night blindness due to atypical retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein concentration in the cerebrospinal fluid. Classic Refsum disease is discussed separately. (See "Neuropathies associated with hereditary disorders", section on 'Refsum disease'.)

Rud syndrome (MIM 308200) is another ichthyosis that presents in infancy. In addition to the skin manifestations, the most common symptoms are hypogonadism and intellectual disability (mental retardation). The index patient suffered from ichthyosis, infantilism, hypogonadism, small stature, epilepsy, macrocytic anemia, tetany, and polyneuritis [35].

Chanarin-Dorfman syndrome (MIM #275630), also known as neutral lipid storage disease with ichthyosis, is an autosomal recessive disorder characterized by ichthyosis, mild myopathy, and hepatomegaly [36-39] due to mutations in the CGI-58 gene (ABHD5) [40]. Intracellular lipid vacuoles are present in most tissues.

Gaucher disease type 2 (MIM #230900) is an autosomal recessive disorder that results from deficiency of glucocerebrosidase. It is characterized by early onset, typically in the first year after birth, and by rapidly progressive neurologic deterioration. Visceral involvement is extensive and severe. This disorder rarely presents with congenital ichthyosis or "collodion baby." (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Type 2 (GD2)'.)

Multiple sulfatase deficiency (MIM #272200) is an autosomal recessive disorder caused by mutations in the sulfatase modifying factor 1 gene (SUMF1) [41-43]. Affected patients develop enzymatic and phenotypic features of multiple individual sulfatase deficiencies, including features of metachromatic leukodystrophy due to arylsulfatase A deficiency, and ichthyosis due to steroid sulfatase deficiency.

MANAGEMENT — There is no cure for SLS. Management involves therapies directed towards controlling ichthyosis, spastic paraparesis, contractures, seizures, and ocular problems. Reductions in quality of life for patients and caregivers have been attributed to problems with mobility and skin care [44]. The same study also reported bulbar and feeding problems, such as drooling, difficulty chewing, and choking, in 75 percent of respondents, although these did not result in lower respiratory infections.

Most children with SLS require a broad range of interventions as follows:

Physical therapy and rehabilitation including mobility and postural support

Speech and language therapy

Clinical swallow evaluation by a speech and language pathologist

Occupational therapy

Educational assistance

Behavioral intervention

Family counseling and support

The evaluation and management of intellectual disability (mental retardation) is discussed separately. (See "Intellectual disability in children: Evaluation for a cause" and "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

Intrathecal baclofen therapy may reduce spasticity and improve function, as reported in two patients with SLS [45]. Some children may benefit from surgical procedures for spasticity and joint contractures [46].

Recurrent seizures are managed with standard anticonvulsants. General recommendations for the evaluation and management of seizures are discussed separately. (See "Overview of the management of epilepsy in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

Gene therapy is under investigation as a possible treatment option for SLS. In a preliminary study, delivery of a recombinant viral vector containing the human complementary DNA (cDNA) of functional fatty aldehyde dehydrogenase (FALDH) into keratinocytes derived from patients with SLS restored FALDH activity [47]. Further research is needed to determine the clinical utility of this method as a treatment for SLS.

Skin care — Ichthyosis and pruritus are treatable but require constant attention and care [18]. These cutaneous symptoms are managed with keratolytic agents and measures to maintain skin hydration, including daily water baths and topical moisturizing creams [22]. Moisturizers include preparations that contain urea or lactate (such as lactic acid with ammonium hydroxide) and come in different vehicles and strengths.

Topical retinoids have been used successfully to treat the ichthyosis in children and adults [48]; however, their use is limited due to adverse effects. In one study of eight children (ages 3 to 18 years), treatment with oral acitretin was associated with improvement in the overall dry skin score and specified symptom sum score (a measure of scaling, erythema, texture, and fissures) [49]. In turn, improvements in skin also had a positive impact on patient and caregiver quality of life and enhanced physical therapy sessions. The initial dose of acitretin was 0.5 mg/kg, which was subsequently lowered to 0.25 mg/kg (10 to 25 mg acitretin) every other day after clinical effect. Over 12 to 16 months of treatment, acitretin was well tolerated, with only dry mouth and inflamed lips requiring topical moisturizers on the higher dose in five patients. However, oral acitretin carries several black box warnings from the US Food and Drug Administration (FDA). Acitretin may affect growth and the skeletal system, cause severe hepatotoxicity, and is a teratogenic.

For additional information on side effects and monitoring of acitretin, refer to the Lexicomp drug information monograph included within UpToDate.

Zileuton, a drug that inhibits the synthesis of leukotriene B4, has been used to treat pruritus in patients with SLS. However, evidence of benefit is limited to small studies [50-52]. A randomized placebo-controlled trial of zileuton that included 10 patients with SLS did not show efficacy overall, but one patient in the active treatment group showed substantial improvement [52]. In a small case series, pruritus was improved at three months in four of five patients with SLS (14 to 21 years old) who were treated with zileuton 600 mg three times daily for the first six weeks and 600 mg four times daily for the last six weeks of the study. However, a subsequent longitudinal study (0.5 to 10 years on treatment) did not show improvements in the neurologic or dermatologic manifestations of disease [53].

PROGNOSIS — Sjögren-Larsson syndrome (SLS) is considered a static leukoencephalopathy; in most cases, the disease is not neurodegenerative, and there is usually no loss of acquired skills. Most patients survive until adulthood [18]. In rare cases, however, children with SLS may exhibit a severe, progressive neurodegenerative course associated with or triggered by infection or by poorly controlled seizures and characterized by a loss of cognitive and physical abilities during childhood [54].

SUMMARY AND RECOMMENDATIONS

Sjögren-Larsson syndrome (SLS) is a disorder of fatty alcohol metabolism caused mutations in the ALDH3A2 gene that encodes for the enzyme fatty aldehyde dehydrogenase (FALDH). Lipid accumulation is the probable mechanism of cutaneous and neurologic disease in SLS. (See 'Pathogenesis' above.)

SLS is associated with the following characteristic clinical features:

Ichthyosis and pruritus

Spastic diplegia or quadriplegia

Intellectual disability (mental retardation)

Ocular abnormalities: photophobia, macular degeneration with retinal crystals, and decreased visual acuity

Leukoencephalopathy

The dermatologic features are typically the earliest presenting symptoms. Severe pruritus is nearly universal in SLS. (See 'Clinical features' above.)

Brain magnetic resonance imaging (MRI) shows delayed myelination with high signal on T2-weighted imaging in the periventricular white matter with either frontal or parieto-occipital predominance. (See 'Neuroimaging' above.)

The diagnosis of SLS can be confirmed by sequence analysis of the ALDH3A2 gene that encodes FALDH and/or by demonstrating FALDH deficiency in cultured skin fibroblasts or leukocytes. (See 'Diagnosis' above.)

In the neonatal period and early infancy, the differential diagnosis of SLS includes the primary ichthyoses, particularly X-linked ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma. Once neurologic symptoms have developed, neuroichthyotic disorders must be considered. (See 'Differential diagnosis' above.)

There is no cure for SLS. However, most patients survive until adulthood. Management involves therapies directed towards controlling ichthyosis, spastic paraparesis, contractures, seizures, and ocular problems. The spastic paraparesis and mild to moderate intellectual disability (mental retardation) that occurs with SLS are addressed by multidisciplinary interventions and educational assistance. (See 'Management' above.)

The cutaneous symptoms of SLS are treatable with keratolytic agents and measures to maintain skin hydration, including daily water baths and topical moisturizing creams. Limited evidence suggests that treatment with oral acitretin is associated with improvement in ichthyosis and dry skin, but the drug is teratogenic and has the potential for serious adverse effects including hepatotoxicity. (See 'Skin care' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alan K Percy, MD, and Raphael Schiffmann, MD, MHSc, FAAN, who contributed to earlier versions of this topic review.

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