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.

Small touches to big walks -the impact of rehabilitation on Sjögren-Larsson syndrome: A case report.

Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disorder characterized by the presence of congenital ichthyosis, spasticity, and mental retardation. As with other rare genetic diseases, treatment is mainly symptomatic. Due to the absence of definitive treatment, lifelong follow-up and support of patients are important to improve the quality of life. A 7-year-old female child who was diagnosed as having SLS was referred to the rehabilitation clinic. After 20 sessions of a rehabilitation program, she started walking independently with the additional contribution of ankle-foot orthoses (AFOs). The contribution of the short-term rehabilitation approach and especially the administration of AFOs to the independence level of the patient is emphasized herein.

Compound heterozygous mutations in the ALDH3A2 gene cause Sjögren-Larsson syndrome: a case report.

Purpose: Sjögren-Larsson syndrome is a rare, autosomal, recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene, which encodes the fatty aldehyde dehydrogenase enzyme. Deficiency in fatty aldehyde dehydrogenase results in an abnormal accumulation of toxic fatty aldehydes in the brain and skin, which cause spasticity, intellectual disability, ichthyosis, and other clinical manifestations. We present the clinical features and mutation analyses of a case of SLS.Materials and Methods: The family history and clinical data of the patient were collected. Genomic DNA was extracted from peripheral blood samples of the patient and her parents, and next-generation sequencing was performed. The candidate mutation sites that required further validation were then sequenced by Sanger sequencing. Bioinformatics software PSIPRED and RaptorX were used to predict the secondary and tertiary structures of proteins.Results: The patient, a five-year-old girl with complaints of cough for three days and intermittent convulsions for seven hours, was admitted to the hospital. Other clinical manifestations included spastic paraplegia, mental retardation, tooth defects, and ichthyosis. Brain magnetic resonance imaging showed periventricular leukomalacia. Genetic screening revealed compound heterozygous mutations in the ALDH3A2 gene: a frameshift mutation c.779delA (p.K260Rfs*6) and a missense mutation c.1157A > G (p.N386S). Neither of the ALDH3A2 alleles in the compound heterozygote patient were able to generate normal fatty aldehyde dehydrogenase, which were likely responsible for her phenotype of Sjögren-Larsson syndrome.Conclusion: The compound heterozygous mutations found in the ALDH3A2 gene support the diagnosis of Sjögren-Larsson syndrome in the patient and expand the genotype spectrum of the gene.

Next-generation sequencing through multi-gene panel testing for diagnosis of hereditary ichthyosis in Chinese.

Inherited ichthyoses are a heterogeneous group of rare disorders related to over 40 genes. To identify underlying molecular causes in inherited ichthyosis among Chinese and to correlate genotype and phenotype, 35 probands clinically diagnosed inherited ichthyosis, except ichthyosis vulgaris and X-linked ichthyosis, were included in our study. Molecular analysis was performed using next-generation sequencing (NGS) through multi-gene panel testing targeting all ichthyosis-related genes. Genetic variants causative for the ichthyosis were identified in 32 of 35 investigated patients. In all, 43 causative mutations across 12 genes were disclosed, including 16 novel variants. Thirteen keratinopathic ichthyosis, fourteen autosomal recessive congenital ichthyosis (ARCI) including one caused by mutations in SDR9C7, and five syndromic ichthyoses were confirmed. Four probands, with presumptive ARCI, turned out to be keratinopathic ichthyosis (2), neutral lipid storage disease (1), and Sjogren-Larsson syndrome (1), respectively. Next-generation technology has been demonstrated to be an effective tool in diagnosing inherited ichthyosis constituting a diverse group of cornification disorders. Our study further expands mutation spectrum and clinical phenotype associated with inherited ichthyosis in Chinese.

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.

Síndrome de Sjögren-Larsson: Reporte de caso pediátrico / Sjögren-Larsson syndrome: Pediatric case report

El síndrome de Sjogren-Larsson se caracteriza por retardo mental, ictiosis congènita y diplejía o cuadriplejía espástica. El defecto primario en este síndrome es la mutación del gen ALDH3A2, que codifica la enzima aldehído deshidrogenasa grasa y causa una deficiencia enzimática que produce una acumulación de alcoholes y aldehídos grasos en los tejidos que comprometen la integridad de la membrana celular, cuyos efectos pueden observarse en la piel, los ojos y el sistema nervioso central. El diagnóstico se realiza por medio de la cuantificación de la actividad de la enzima. Se describe el caso de una paciente con signos clínicos patognomónicos del síndrome de Sjogren-Larsson, cuyo diagnóstico se realizó por medio de la cuantificación de la actividad enzimática en un cultivo de fibroblastos. Además, tomando en cuenta el árbol genealógico de la paciente, se realizó el estudio en los padres y un hermano con signos sugestivos del síndrome de Sjogren-Larsson.

Sjogren-Larsson syndrome is characterized by congenital ichthyosis, mental retardation and spastic diplegia or quadriplegia. The primary defect in this syndrome is mutation of ALDH3A2 gen that codes for the fatty aldehyde dehydrogenase. Deficiency of this enzyme causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity. Skin, eyes, and the central nervous system are affected latter. The diagnosis is carried out through the cuantification of the enzyme activity.

[Sjögren-Larsson syndrome: Pediatric case report]. / Síndrome de Sjögren-Larsson: Reporte de caso pediátrico.

Sjogren-Larsson syndrome is characterized by congenital ichthyosis, mental retardation and spastic diplegia or quadriplegia. The primary defect in this syndrome is mutation of ALDH3A2 gen that codes for the fatty aldehyde dehydrogenase. Deficiency of this enzyme causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity. Skin, eyes, and the central nervous system are affected latter. The diagnosis is carried out through the cuantification of the enzyme activity. This case report describes the diagnosis of a clinical syndrome with symptoms of Sjogren-Larsson syndrome by the quantification of the enzymatic activity in a culture of fibroblasts. Also, taking into account the genealogy of the patient, the study was conducted in the parents and a brother with signs suggestive of Sjogren-Larsson syndrome.

El síndrome de Sjogren-Larsson se caracteriza por retardo mental, ictiosis congènita y diplejía o cuadriplejía espástica. El defecto primario en este síndrome es la mutación del gen ALDH3A2, que codifica la enzima aldehído deshidrogenasa grasa y causa una deficiencia enzimática que produce una acumulación de alcoholes y aldehídos grasos en los tejidos que comprometen la integridad de la membrana celular, cuyos efectos pueden observarse en la piel, los ojos y el sistema nervioso central. El diagnóstico se realiza por medio de la cuantificación de la actividad de la enzima. Se describe el caso de una paciente con signos clínicos patognomónicos del síndrome de Sjogren-Larsson, cuyo diagnóstico se realizó por medio de la cuantificación de la actividad enzimática en un cultivo de fibroblastos. Además, tomando en cuenta el árbol genealógico de la paciente, se realizó el estudio en los padres y un hermano con signos sugestivos del síndrome de Sjogren-Larsson.

Late-Stage Sjögren-Larsson Syndrome Maculopathy Imaged With OCT Angiography.

Three adult siblings with Sjögren-Larsson syndrome (SLS) demonstrated signs of late-stage SLS maculopathy, including intraretinal crystals, atrophic changes, and lipofuscin deposition. This first report of SLS maculopathy imaged with optical coherence tomography angiography revealed decreased retinal capillary density, vessel dilation, and increased flow voids in the superficial and deep capillary plexuses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e78-e82.].

Clinical, biochemical, and genetic aspects of Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is caused by an autosomal recessive mutation in ALDH3A2, which encodes the fatty aldehyde dehydrogenase responsible for the metabolism of long-chain aliphatic aldehydes and alcohols. The pathophysiologic accumulation of aldehydes in various organs, including the skin, brain, and eyes, leads to characteristic features of ichthyosis, intellectual disability, spastic di-/quadriplegia, and low visual acuity with photophobia. The severity of the clinical manifestations thereof can vary greatly, although most patients are bound to a wheelchair due to contractures. To date, correlations between genotype and phenotype have proven difficult to document due to low disease incidence and high heterogenetic variability in mutations. This review summarizes the clinical characteristics of SLS that have been found to contribute to the prognosis thereof, as well as recent updates from genetic and brain imaging studies. In addition, the differential diagnoses of SLS are briefly illustrated, covering cerebral palsy and other genetic or neurocutaneous syndromes mimicking the syndrome.

Sjögren-Larsson syndrome: definitive diagnosis on magnetic resonance spectroscopy.

Sjögren-Larsson syndrome (SLS) is a rare autosomal-recessive neurocutaneous disorder comprising a triad of ichthyosis, mental retardation, and spastic diplegia or quadriplegia. It has rarely been reported in Asian and Indian populations. We report the case of an Indian patient with SLS who presented with the classical clinical triad and demonstrated characteristic findings on magnetic resonance spectroscopy. In resource-restricted settings where enzymatic and genetic analyses are not available, magnetic resonance spectroscopy serves as a useful adjunct in confirming the diagnosis of SLS.

Cerebral lipid accumulation in Chanarin-Dorfman Syndrome.

Chanarin-Dorfman Syndrome (CDS) is caused by a defect in the CGI-58/ABHD5 gene resulting in a deficiency of CGI-58 and in intracellular accumulation of triacylglycerol in skin and liver. Patients are mainly characterized by congenital ichthyosis, but the clinical phenotype is very heterogeneous. Distinct brain involvement has never been described. We present a clinical description of two patients with congenital ichthyosis. On suspicion of Sjögren-Larsson syndrome (SLS) single-voxel 1H-MR spectroscopy of the brain was performed and biochemical testing of fatty aldehyde dehydrogenase (FALDH) to establish this diagnosis gave normal results. Vacuolisation in a peripheral blood smear has led to the CDS suspicion. In both patients the diagnosis CDS was confirmed by ABHD5 mutation analysis. Interestingly, a clear lipid accumulation in the cerebral white matter, cortex and basal ganglia was demonstrated in both CDS-patients. These results demonstrate, for the first time, cerebral involvement in CDS and give new insights in the complex phenotype. Since the clinical implications of this abnormal cerebral lipid accumulation are still unknown, further studies are warranted.