Clinical manifestations

Presentation and course

The clinical features of Sjögren-Larsson syndrome consist of three major symptoms: (1) ichthyosis, (2) intellectual disability, and (3) spastic diplegia or tetraplegia (41; 47; 27). These three clinical features were seen in virtually all of the Swedish patients; the lack of even a single major symptom has made the diagnosis suspect (17).

The neurologic symptoms of Sjögren-Larsson syndrome become evident within the first three years of life. Developmental delay, particularly in achieving motor and speech milestones, is usually noted prior to two years of age. Spastic diplegia is much more common than tetraplegia, and contractures of the lower extremities are usually evident by mid-childhood (49). Many patients never gain the ability to walk, and those that do walk often require leg braces or other assisting devices. The degree of cognitive impairment tends to correlate with the severity of spasticity (18). In a study of the Swedish Sjögren-Larsson syndrome population, two thirds of the patients had IQs lower than 50. Most patients have dysarthria and oral-facial motor abnormalities, but severe dysphagia or need for feeding tubes is rarely encountered (12). Drooling, choking on solid foods, and chewing problems, however, are seen in some patients (42). One third of the patients develop seizures, either isolated or as a recurrent disorder (47; 18). Brain MRI often shows widespread white matter disease involving periventricular regions, parietal and frontal lobes, and corpus callosum, suggesting delayed myelination and dysmyelination. MR spectroscopy reveals abnormal signals consistent with lipid accumulation in affected white matter (53). Nerve conduction studies are normal (18).

The ichthyosis in Sjögren-Larsson syndrome is usually apparent at the time of birth (19). The skin is initially erythematous and hyperkeratotic, and some infants are born with a parchment-like collodion membrane on their skin. Erythema fades over time, leaving behind an ichthyotic appearance. A small proportion of patients first develop ichthyosis after several months of age. The ichthyosis tends to be mild to moderate in severity. Scales can be fine and dandruff-like, larger and more lamellar-like, or even thick and dark brown in appearance. The ichthyosis is generalized in distribution, and typically affects the flexures, trunk, abdomen, back, extremities, nape of the neck, and dorsal areas of the hands and feet. Less commonly affected are the palms and soles, whereas the central face is usually spared. Pruritus is a frequent complaint. Diminished sweating occurs in a minority of patients (19). Alopecia is not a feature of Sjögren-Larsson syndrome nor are hair or nail abnormalities.

Photophobia is a common symptom in Sjögren-Larsson syndrome, and retinal abnormalities are typically seen (09). The most consistent retinal finding is a distinctive crystalline maculopathy with glistening yellowish-white dots in the perifoveal areas and macular degeneration (20). Using optical coherence tomography, the inclusions appear as focal hyperreflectivities in the perifoveal ganglion cell layer and the inner plexiform layer (11). Cystoid foveal degeneration is also seen. Image analysis of serial retinal photos taken over 1 to 3 years demonstrates the appearance of new inclusions and the disappearance of some inclusions, suggesting that the inclusions have a dynamic characteristic (01). Retinal pigmentary changes have also been seen in some patients. Myopia is common, but vision is usually spared.

Most patients with Sjögren-Larsson syndrome have short stature, due in part to leg contractures and decreased leg growth rather than general growth delay. Kyphoscoliosis is not uncommon, particularly in severely spastic patients.

There can be considerable clinical variation in Sjögren-Larsson syndrome, even among patients within a kindred. One unusual family had three affected siblings who showed no significant intellectual disability but had diverse severity of spasticity and cutaneous symptoms (26). Another Arab family with six affected adult siblings exhibited significant differences in the severity of neurologic symptoms and white matter disease on brain MRI (24). Two Honduran patients carried the identical disease-causing mutation but exhibited diverse neurologic phenotypes; one patient had an unusual neurodegenerative course with spastic tetraplegia whereas the other patient had the more typical static diplegia (05). These findings suggest the presence of modifier genes or environmental factors influencing disease severity. Patients of average intellect and mild spasticity have been recognized with no apparent genotype-phenotype explanation (45).

Prognosis and complications

Patients with Sjögren-Larsson syndrome are often born prematurely (43). Life expectancy was initially reported to be decreased (41), but more recent experience indicates that most patients survive well into adulthood (17). Patients have been noted to lose the ability to ambulate due to progressive contractures. Sjögren-Larsson syndrome is not a typical neurodegenerative disease; however, reports have described several patients who have had an unusual neuroregressive course during childhood and adolescence (05; 04; 22). Most of these patients had uncontrolled seizure disorders, but in one case, a 2-year-old child developed progressive loss of neurologic function after suffering a prolonged febrile illness (50).The ichthyosis does not appear to worsen with age.

Quality of life is reduced in most patients due to itchy skin, reduced mobility, and dependency (42).

Clinical vignette

A male infant was born after an uneventful 36-week pregnancy to a 26-year-old female. Birth weight was six pounds nine ounces. Shortly after birth he was noted to have dry, flaking skin. He fed well, however, and was discharged from the hospital after several days. When his scaly skin failed to resolve after several weeks, he was referred to a dermatologist who noted moderate generalized hyperkeratosis involving the trunk, extremities, and scalp, but sparing the face, palms, and soles. He was diagnosed as having congenital ichthyosis, and the skin subsequently improved with frequent baths and lactic acid lotion. At four weeks of age, he developed occasional jerking episodes that became more frequent over the next several months. The child was hospitalized at four months of age for seizures characterized as asymmetric left-sided jerking episodes with right-sided clenched fists and eye deviation. The seizures were often associated with lip smacking, thrusting of his tongue, and eye blinking. Partial complex seizures with secondary generalized convulsions were diagnosed, and the child’s seizures subsequently responded to phenobarbital therapy. Neurologic examination revealed hyperreflexia in the lower extremities with bilateral ankle clonus and leg scissoring. Brain MRI showed possible thinning of the corpus callosum, but no other white matter abnormalities. Because of the presence of spastic diplegia and ichthyosis, the diagnosis of Sjögren-Larsson syndrome was entertained.

Subsequent enzymatic testing of a fibroblast culture revealed a profound deficiency in the activity of fatty aldehyde dehydrogenase and fatty alcohol:NAD+ oxidoreductase, confirming the diagnosis of Sjögren-Larsson syndrome.

A trial of dietary medium-chain triglyceride supplementation failed to result in improvement of the ichthyosis or spasticity. Over the subsequent years, the patient showed delay in achieving motor and language milestones. He spoke his first words at three and a half years of age and used complete sentences at five years of age. At five and a half years of age, the patient was unable to walk or stand independently. Physical examination was significant for generalized ichthyosis, spastic diplegia, and moderate mental retardation intellectual disability. Brain MRI showed white matter disease in the frontal and parietal lobes.

Biological basis

Etiology and pathogenesis

Sjögren-Larsson syndrome is caused by mutations in the gene encoding fatty aldehyde dehydrogenase (ALDH3A2) (06). To date, more than 90 different mutations have been identified, including missense and nonsense mutations, deletions, insertions, and splice-site alterations (52). Large contiguous gene deletions involving ALDH3A2 and neighboring genes have been found in some patients (08). Most mutations are unique to a family, but several common mutations have been found in patients originating from Europe (07; 40; 30), the Mideast (30) and Brazil (02). Many patients of Swedish and northern European descent carry an identical missense mutation (c.943C> T; Pro315Ser), and haplotype studies indicate that they share a common ancestor (07; 40). Most Swedish patients are homozygous for this mutation; this is consistent with a founder effect and their consanguineous history. A second deletion mutation, c.1297-1298delGA, is frequently seen in European patients (30). Approximately one half of European patients carry c.943C>T or c.1297-1298delGA. Sjögren-Larsson syndrome is inherited in an autosomal recessive fashion (41), and the gene is localized to chromosome 17p11.2.

Patients with Sjögren-Larsson syndrome have an impaired ability to oxidize long-chain fatty aldehydes and alcohols due to deficient activity of fatty aldehyde dehydrogenase. Fatty aldehydes are generated from several lipids, including metabolism of sphingolipids, various fatty alcohols, ether glycerolipids, leukotriene B4, and possibly other eicosanoid lipids (28). Because of deficient fatty aldehyde dehydrogenase, which is a component of the fatty alcohol:NAD+ oxidoreductase enzyme complex that is responsible for metabolizing fatty alcohols, patients with Sjögren-Larsson syndrome also exhibit defective fatty alcohol oxidation (35; 31). Enzyme activity is deficient in cultured skin fibroblasts, leukocytes, keratinocytes, fetal-derived amniocytes, and cultured chorionic villi cells (33; 27).

Fatty alcohol:NAD+ oxidoreductase is a complex enzyme consisting of fatty alcohol dehydrogenase and fatty aldehyde dehydrogenase components, which sequentially oxidize fatty alcohol to fatty aldehyde and fatty acid. Patients with Sjögren-Larsson syndrome are selectively deficient in the fatty aldehyde dehydrogenase component (31). As expected for an autosomal recessive disease, heterozygote carriers for Sjögren-Larsson syndrome have about 50% of the normal fatty aldehyde dehydrogenase activity and do not exhibit symptoms (23).

The only general pathologic reports of Sjögren-Larsson syndrome predate discovery of the enzyme defect and involve patients diagnosed clinically, therefore raising uncertainty about the diagnosis (03; 46). A consistent neuropathological finding in the two autopsied cases, however, is the loss of myelin, either of a widespread distribution or particularly prominent in the centrum semiovale, pyramidal tracts, and frontal lobes. In one patient, ballooning of myelin sheaths was noted in areas of myelin loss and near blood vessels throughout the white matter, and sudanophilic fat droplets were accumulated throughout the gray matter (46). In the cervical spinal cord, this patient also showed demyelination of the crossed and anterior corticospinal tracts and the vestibulospinal tracts. One 68-year-old patient, genetically related to the original Swedish cohort, had a mild loss of cerebellar cortical neurons (51). A second Swedish 73-year-old patient, who developed parkinsonian signs at 54 years of age, showed degeneration of the substantia nigra together with widespread loss of myelin and the presence of macrophages containing myelin breakdown products.

The neuropathological findings in a genetically confirmed 65-year-old patient were reported (45). The patient had a lack of myelin in hemispheric deep white matter and long white matter tracts in the brainstem and spinal cord, but no reduction in the number of oligodendrocytes. The cerebral cortex was mildly gliotic without neuronal dropout or microglia activation. In cerebellar white matter, however, activated microglia and scattered macrophages were found in perivascular spaces. In cerebellar cortex, a mild reduction in Purkinje cells and granular neurons were seen. No white matter abnormalities were seen in the optic nerve, optic chiasm, or optic tracts.

The pathogenesis of the retinal abnormalities in Sjögren-Larsson syndrome is still unknown (09). The biochemical composition of the distinctive perifoveal crystalline inclusions is not known. An unusual lack of macular pigment occurs in the retina, which may increase susceptibility to photo-oxidative stress and photoreceptor degeneration (48). Thinning of the inner and outer nuclear cell layers in the retina occurs, which is consistent with cell loss (16).

The pathogenesis of the retinal findings in Sjögren-Larsson syndrome is still unknown (09). Studies using optical coherence tomography demonstrated focal hyperreflectivities in the perifoveal ganglion cell layer and the inner plexiform layer that are associated with the glistening white dots (11). Cystoid foveal degeneration was also seen. In addition, thinning of the inner and outer nuclear cell layers in the retina occurs (16). An unusual lack of macular pigment may increase susceptibility to photo-oxidative stress and photoreceptor degeneration (48).

The histopathology of the skin in Sjögren-Larsson syndrome is more thoroughly described than that of any other organ (15; 37). Skin biopsies show hyperkeratosis with a basket-weave appearance, papillomatous changes, and acanthosis. The granular layer tends to be mildly thickened, but it can also be normal or even diminished in size. Some patients show a slight mononuclear cell infiltration in the upper dermis. Electron microscopy of the skin reveals the presence of electron-lucent clefts and membranous inclusions in the cornified layer. Membranous inclusions can also be seen in granular cells of both affected and unaffected skin. Many lamellar bodies appear empty or structurally abnormal and fail to secrete their membrane contents into the boundary between the stratum granulosum and stratum corneum. As a result, the stratum corneum membrane arrays are deficient and contain nonlamellar lipid inclusions, which results in a defective epidermal water barrier (37). Thymidine-labeling studies of the skin in Sjögren-Larsson syndrome indicate a hyperproliferative state, which probably represents an attempt to restore the defective water barrier (19).

It is not yet established how the enzymatic defect leads to neurologic and cutaneous symptoms in Sjögren-Larsson syndrome (28). It is thought that tissue storage of fatty alcohol, fatty aldehyde, or their metabolic products are intimately involved in the pathogenesis. Elucidation of the biochemical mechanisms, however, is complicated by the involvement of fatty aldehyde dehydrogenase in several lipid pathways that generate fatty aldehydes, including metabolism of various fatty alcohols, ether glycerolipids, leukotriene B4, and possibly other eicosanoid lipids. Proton magnetic resonance spectroscopy of the brain shows an abnormal spectrum suggestive of lipid storage in cerebral white matter that increases during the first few years of life and then plateaus (53). This suggests that lipid storage is a progressive process associated with myelination.

There is growing evidence that accumulation of fatty alcohols and metabolically-related ether glycerolipids are involved in the pathogenesis of Sjögren-Larsson syndrome. Affected patients accumulate 16- and 18-carbon fatty alcohols in plasma (32) and in all cultured cells examined so far. In cultured skin keratinocytes, fatty alcohols that cannot be metabolized are diverted into biosynthetic pathways for neutral alkyl glycerolipids (34), and cutaneous scales (stratum corneum) from patients accumulate approximately almost 100-fold greater amounts of these lipids than control skin (38). Cutaneous scales are also deficient in certain ceramide lipids that are essential for the epidermal water barrier (25). These lipid changes may account for the abnormal membranes in stratum corneum seen on electron microscopy and the defective epidermal water barrier. Lipidomic studies of the autopsied brain of one patient with Sjögren-Larsson syndrome revealed large accumulation of very long chain fatty alcohols (C18-C24) and homologous ether glycerolipids (44). These lipids probably account for the lipid peaks seen in myelin with magnetic resonance spectroscopy. Importantly, both stratum corneum and myelin contain stacked multi-lamellar membranes that are critical for tissue function, and disruption of these membranes by excessive lipid accumulation is expected to have deleterious functional effects.

In contrast to fatty alcohols and ether glycerolipids, the contribution of fatty aldehydes to the pathogenesis of Sjögren-Larsson syndrome is unclear. Cultured fibroblasts from patients have been found to accumulate fatty aldehyde-modified phosphatidylethanolamine (21). Phosphatidylethanolamine is a prominent phospholipid in brain, and this aldehyde-modified lipid (if it accumulates in nervous tissue from affected patients) could have profound effects on membrane function. Moreover, fatty aldehyde dehydrogenase normally acts to metabolize aliphatic aldehydes derived from degradation of ether glycerolipids (ie, plasmalogens) and sphingolipids that are prominent in myelin, leading to speculation that the white matter abnormalities in this disease arise in part from formation of aldehyde-modified myelin lipids and proteins (29).

Epidemiology

Patients with Sjögren-Larsson syndrome have been diagnosed worldwide and in most ethnic and racial groups (47). The largest population of patients with Sjögren-Larsson syndrome resides in northern Sweden in the counties of Vasterbotten and Norbotten (17). The prevalence of the disease in Vasterbotten is 8.3 per 100,000, whereas in the whole country of Sweden the prevalence is 0.4 per 100,000. The high prevalence of Sjögren-Larsson syndrome in northern Sweden is probably due to founder effects. Sjögren and Larsson were able to trace the lineage of their patients back to several ancestors living in the 1700s (41). The second highest prevalence of Sjögren-Larsson syndrome is in the Mideast.

Prevention

Prenatal diagnosis offers the only means for prevention of Sjögren-Larsson syndrome. The diagnosis of affected fetuses can be accomplished in the first and second trimester by enzymatic studies of cultured chorionic villi cells and amniocytes, respectively (33). If the specific mutation is known in a family, prenatal diagnosis may also be performed by DNA mutation analysis (39).

Differential diagnosis

Confusing conditions

The diagnosis of Sjögren-Larsson syndrome should be entertained in any patient with spasticity and intellectual disability in combination with ichthyosis or dry skin. The cutaneous symptoms usually bring the patient to medical attention in the newborn period. Prior to the onset of neurologic symptoms, the differential diagnosis includes all other forms of congenital ichthyosis. The ichthyosis alone may be sufficient to justify genetic or enzymatic studies at that time because the intellectual disability and spasticity develop later in the first or second year. After neurologic symptoms develop, however, the differential diagnosis includes other neuro-ichthyotic disorders, such as Refsum disease, neutral lipid storage disease, multiple sulfatase deficiency, ELOVL4 deficiency, and infantile Gaucher disease (36).

Diagnostic workup

The definitive diagnostic test for Sjögren-Larsson syndrome is demonstration of mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase or measurement of either fatty alcohol:NAD+ oxidoreductase or fatty aldehyde dehydrogenase activity in cultured skin fibroblasts or leukocytes. In cultured fibroblasts, activity of fatty alcohol:NAD+ oxidoreductase in 47 patients ranged from 2% to 16% of mean normal activity using octadecanol as substrate (27). Activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase was comparably deficient. DNA diagnosis by sequencing the ALDH3A2 gene will detect mutations in greater than 95% of patients with enzymatically confirmed Sjögren-Larsson syndrome. Other clinical tests, including brain MRI and proton MR spectroscopy, are not definitive alone but may support the diagnosis of Sjögren-Larsson syndrome. The finding of glistening white dots in the perifoveal region of the retina may be pathognomonic for this disease, but they don’t usually appear until several years of age and are apparently missing in some genetically confirmed cases.

Histological examination of a skin biopsy may show characteristic finding of hyperkeratosis, papillomatosis, acanthosis, and thickened granular layer, but these abnormalities are also seen in other forms of ichthyosis. Neuroimaging, somatosensory evoked potentials, visual evoked potentials, and brainstem evoked potentials are useful in defining the extent of neurologic involvement in an individual patient but do not replace more definitive biochemical or genetic tests.

Management

Effective therapy for the primary neurologic symptoms of Sjögren-Larsson syndrome is limited (27). Seizures, if present, typically respond to standard anticonvulsants. Physical, occupational, and speech therapies are useful to achieve optimal daily function and delay progressive contractures. Orthopedic surgical procedures are often helpful to improve contractures and ambulation. Ankle-foot orthoses, canes, or walkers are usually necessary for optimal ambulation. Although systemic baclofen has limited effectiveness in Sjögren-Larsson syndrome, intrathecal baclofen therapy has been shown to improve spasticity in two affected children (14).

The ichthyosis responds in part to topical keratolytic emollients and moisturizing lotions, which have a temporary effect. The skin improves dramatically with off-label administration of systemic retinoids, but concerns about potential side effects of retinoids on bone growth have limited their use in children. Anecdotal reports that zileuton, which blocks the synthesis of leukotriene B4, improved the pruritus associated with Sjögren-Larsson syndrome were not borne out by a placebo-controlled double-blinded clinical trial of the drug (13). Antihistamines have also proven ineffective for the pruritus.

Treatments on the horizon. Targeted therapeutic approaches that are based on the specific biochemical abnormalities in Sjögren-Larsson syndrome seem most promising (29). The finding that abnormal myelin lipids on MR spectroscopy and retinal crystalline inclusions increase over the first several years of life raises the theoretical possibility that early therapeutic intervention to mitigate lipid accumulation might be beneficial. The topical use of an experimental aldehyde scavenging drug to block formation of potentially harmful aldehyde adducts in the skin was moderately beneficial in a phase 2 clinical trial. Dietary restriction of certain lipids that accumulate in Sjögren-Larsson syndrome seems like a rational approach that should be investigated, however, previous empirical use of lipid modified diets have shown no convincing benefit for patients.

Outcomes

Despite current approaches to treatment, most patients will exhibit the neurocutaneous symptoms of Sjögren-Larsson syndrome throughout life.

Special considerations

Anesthesia

General anesthesia involving 14 patients undergoing 48 anesthetic events with a variety of anesthetic agents was reported to be safe (10). The most common issues were related to the ichthyosis, which led to difficulty in adherence of electrocardiogram leads and intravenous catheter dressings.