Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics.

AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS. METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites. CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

Retinal Capillary Abnormalities in Sjögren-Larsson Syndrome Maculopathy.

Sjögren-Larsson syndrome (SLS) is a neurometabolic disease with a peculiar crystalline maculopathy. It is yet unclear if vascular abnormalities play a role in SLS maculopathy pathogenesis. We used optical coherence tomography angiography (OCT-A) to search for vessel abnormalities in SLS maculopathy. We performed a cross-sectional study in 4 patients (2 males, 2 females, aged 12-36 years) with various stages of SLS maculopathy. Besides OCT-A imaging, a complete ophthalmological examination and additional retinal imaging by transversal and en face spectral domain (SD) OCT were performed. OCT-A images were qualitatively assessed for vascular abnormalities, and imaging was compared to eight eyes of four healthy controls. On OCT-A, all eyes of patients with SLS showed a reduced capillary density around the fovea, and an enlarged foveal avascular zone (FAZ; SLS patients [n = 6 eyes] mean 0.70 mm2 [SD 0.18]; healthy controls [n = 8 eyes] mean 0.34 mm2 [SD 0.07], p = 0.004). In 2 patients, telangiectatic vessels were seen in the deep capillary layer. In conclusion, OCT angiography showed capillary paucity and morphological vessel abnormalities in these 4 patients with SLS.

Disturbed brain ether lipid metabolism and histology in Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid peak in the white matter of patients with SLS, suggesting lipid accumulation in the brain as well. Using histopathology, mass spectrometry imaging, and lipidomics, we studied the morphology and the lipidome of a postmortem brain of a 65-year-old female patient with genetically confirmed SLS and compared the results with a matched control brain. Histopathological analyses revealed structural white matter abnormalities with the presence of small lipid droplets, deficient myelin, and astrogliosis. Biochemically, severely disturbed lipid profiles were found in both white and gray matter of the SLS brain, with accumulation of fatty alcohols and ether lipids. Particularly, long-chain unsaturated ether lipid species accumulated, most prominently in white matter. Also, there was a striking accumulation of odd-chain fatty alcohols and odd-chain ether(phospho)lipids. Our results suggest that the central nervous system involvement in SLS is caused by the accumulation of fatty alcohols leading to a disbalance between ether lipid and glycero(phospho)lipid metabolism resulting in a profoundly disrupted brain lipidome. Our data show that SLS is not a pure leukoencephalopathy, but also a gray matter disease. Additionally, the histopathological abnormalities suggest that astrocytes and microglia might play a pivotal role in the underlying disease mechanism, possibly contributing to the impairment of myelin maintenance.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.

Retinal Morphology in Sjögren-Larsson Syndrome on OCT: From Metabolic Crystalline Maculopathy to Early-Onset Macular Degeneration.

PURPOSE: To study long-term macular changes by spectral-domain (SD) OCT in patients with Sjögren-Larsson syndrome (SLS). DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-two patients with genetically proven SLS (12 female, 10 male; median age, 21 years; range, 3-47 years) were included in the study. One or more SD-OCT scans were available from the period 2008 to 2017. METHODS: Seventeen patients underwent SD-OCT imaging of the macula in 2017. Earlier scans were available of the other 5 patients. The latest available SD-OCT scans were qualitatively assessed for morphologic changes in 19 patients. In addition, retinal layer thickness could be measured in 15 patients. The latest scans were compared with previous scans to assess the course of the disease qualitatively (n = 15 patients) and quantitatively (n = 10 patients). MAIN OUTCOME MEASURES: Macular morphology and retinal layer thickness on SD-OCT scans during the study period. RESULTS: In all patients, abnormal macular morphology was observed in both eyes, already from the youngest age. Intraretinal crystals, visible as hyperreflective dots, were visible in all eyes and located in the retinal nerve fiber layer, inner plexiform layer, and outer plexiform layer. Furthermore, the photoreceptor (PR) layer lacked the physiologic thickness amplification beneath the fovea. Pseudocysts with limited interruption of the underlying PR layer were observed in half of the patients, all younger than 30 years of age. Frank atrophy of the retinal pigment epithelium (RPE) and a neovascular complex were seen in 3 older patients and 1 older patient, respectively. The fovea was significantly thinner compared with healthy controls and decreased even further during the study period. CONCLUSIONS: Macular dystrophy in SLS may initially comprise an arrest in foveal development. Because of the absence of macular pigment, phototoxic damage may then cause central retinal degeneration of the vulnerable macula, marked by the development of pseudocysts. Eventually, the young adult patients may proceed to an early-onset end-stage macular degeneration with frank atrophy of the RPE or neovascularization.

Daily Functioning and Quality of Life in Patients with Sjögren-Larsson Syndrome.

AIM: Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurometabolic disease caused by an enzyme defect in lipid metabolism. Patients suffer from intellectual disability, bilateral spastic paresis, ichthyosis, visual impairment, and photophobia. Knowledge about the meaning of having SLS in daily life is lacking. METHODS: Sixteen parents or caregivers of patients with SLS were asked to fill out online questionnaires about daily functioning, quality of life, feeding and swallowing problems, skin treatment, female hormonal status, and greatest problems. RESULTS: Questionnaires were filled out by parents or caregivers of six children and 10 adult patients, age range 11 to 58 years. The median quality of life score was 73 (range: 26-100). Most often reported problems were itchy skin, reduced mobility, and dependency. Feeding and swallowing problems were reported in 75% of the patients. Mood problems were rarely mentioned. DISCUSSION: Despite the large disruptions of daily functioning, patients with SLS are according to their parents generally content with their quality of life and participation. There was a broad range in reported problems. We found it very useful to systematically ask parents about their children's feelings and needs, to better understand the meaning of living with a complex disorder like SLS.

Understanding fetal factors that contribute to preterm birth: Sjögren-Larsson syndrome as a model.

AIM: Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjögren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjögren-Larsson syndrome is born preterm. METHODS: Data of all known Dutch patients with Sjögren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. RESULTS: Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. CONCLUSIONS: Preterm birth is a hallmark of Sjögren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth.

[A neonate who could not open her eye]. / Een zuigeling die haar oog niet kan openen.

We present a case of a female neonate who was born with a string between the eyelids of one eye. There were no other dysmorfic features. She had an isolated ankyloblepharon filiforme adnatum, a rare congenital malformation of the eyelid.