Sjögren: unique surname, two men, four syndromes and one disease / Sjögren: sobrenome único, dois homens, quatro síndromes e uma doença

Abstract Henrik and Torsten Sjögren (/'ogrƏn/ or SHOH-grƏn) were two Swedish physicians living in the same period, but completely unrelated, except for their notable contributions to Medicine. The first one described keratoconjunctivitis sicca, afterward called Sjögren's syndrome, and a fishing net aspect retinal pigmentation affecting visual acuity, nowadays known as Sjögren reticular dystrophy. The last one contributed to the understanding of Spielmeyer-Sjögren disease, Marinesco-Sjögren, and Sjögren-Larsson syndromes, all related to genetic disorders and neurological symptoms. In this paper, we aim to describe each disorder, in order to avoid any misunderstanding in diagnosis and for historical record.

Resumo Henrik e Torsten Sjögren (/'ogrƏn/ or SHOH-grƏn) foram dois médicos suecos que viveram na mesma época, mas não tinham nenhuma relação entre si, exceto por suas notáveis contribuições à medicina. O primeiro descreveu a ceratoconjuntivite sicca, posteriormente chamada de síndrome de Sjögren, e uma pigmentação da retina com aspecto de rede de pesca que afeta a acuidade visual, hoje conhecida como distrofia reticular de Sjögren. O último contribuiu para a compreensão da doença de Spielmeyer-Sjögren, das síndromes de Marinesco-Sjögren e Sjögren-Larsson, todas relacionadas a distúrbios genéticos e sintomas neurológicos. Neste artigo, pretendemos descrever cada desordem, a fim de evitar qualquer mal-entendido no diagnóstico e para registro histórico.

Sjogren-Larsson syndrome brain volumetric reductions demonstrated with an automated software / Reduções volumétricas cerebrais da síndrome de Sjogren-Larsson demonstradas com um software automatizado

Abstract Background Sjogren-Larsson syndrome (SLS) is a neurocutaneous disease with an autosomal recessive inheritance, caused by mutations in the gene that encodes fatty aldehyde dehydrogenase (ALDH3A2), clinically characterized by ichthyosis, spastic diplegia, and cognitive impairment. Brain imaging plays an essential role in the diagnosis, demonstrating a nonspecific leukoencephalopathy. Data regarding brain atrophy and grey matter involvement is scarce and discordant. Objective We performed a volumetric analysis of the brain of two siblings with SLS with the aim of detecting deep grey matter nuclei, cerebellar grey matter, and brainstem volume reduction in these patients. Methods Volume data obtained from the brain magnetic resonance imaging (MRI) of the two patients using an automated segmentation software (Freesurfer) was compared with the volumes of a healthy control group. Results Statistically significant volume reduction was found in the cerebellum cortex, the brainstem, the thalamus, and the pallidum nuclei. Conclusion Volume reduction in grey matter leads to the hypothesis that SLS is not a pure leukoencephalopathy. Grey matter structures affected in the present study suggest a dysfunction more prominent in the thalamic motor pathways.

Resumo Antecedentes A Síndrome de Sjogren-Larsson (SSL) é uma doença neurocutânea de herança autossômica recessiva, causada por mutações no gene que codifica a aldeído graxo desidrogenase (ALDH3A2), caracterizada clinicamente por ictiose, diplegia espástica e comprometimento cognitivo. A imagiologia cerebral desempenha um papel essencial no diagnóstico, demonstrando uma leucoencefalopatia inespecífica. Dados sobre atrofia cerebral e envolvimento da substância cinzenta são escassos e discordantes. Objetivo Realizamos uma análise volumétrica do cérebro de dois irmãos com SLS com o objetivo de detectar núcleos profundos de substância cinzenta, substância cerebral cinzenta e redução do volume do tronco encefálico nestes pacientes. Métodos Os dados de volume obtidos da ressonância magnética (RM) cerebral dos dois pacientes usando um software de segmentação automática (Freesurfer) foram comparados com os volumes de um grupo controle saudável. Resultados Redução de volume estatisticamente significativa foi encontrada no córtex do cerebelo, no tronco cerebral, no tálamo e nos núcleos pálidos. Conclusão A redução do volume da substância cinzenta leva à hipótese de que a SSL não é uma leucoencefalopatia pura. As estruturas da substância cinzenta afetadas no presente estudo sugerem uma disfunção mais proeminente nas vias motoras talâmicas.

Sjögren-Larsson Syndrome: A Rare Presentation With Developmental Delay.

Sjögren-Larsson syndrome (SLS) is a rare, inherited disorder passed down through families in an autosomal recessive pattern. Its main characteristics are spastic diplegic paralysis, congenital ichthyotic hyperkeratosis, and mild-to-moderate mental retardation. Lack of activity of microsomal fatty aldehyde dehydrogenase (FALDH) or its complete absence is the primary cause of this syndrome, leading to the build-up of fatty aldehydes and fatty alcohols in the body, particularly in the skin. In order to provide the best care for patients, educating them about the management of dry skin and offering genetic counseling are essential. We hereby present a case of an eight-year-old patient with spastic diplegia, congenital ichthyosis, and intellectual disability diagnosed with SLS.

Ceramide profiling of stratum corneum in Sjögren-Larsson syndrome.

BACKGROUND: Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. OBJECTIVES: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. METHODS: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. RESULTS: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. CONCLUSION: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

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.

Sjögren-Larsson syndrome: A biochemical rationale for using aldehyde-reactive therapeutic agents.

Sjögren-Larsson syndrome (SLS) is a neurocutaneous disease caused by mutations in ALDH3A2 that result in deficient fatty aldehyde dehydrogenase (FALDH) activity and impaired fatty aldehyde and fatty alcohol oxidation. The pathogenesis of SLS is thought to involve accumulation of long-chain fatty aldehydes and alcohols and/or metabolically-related ether glycerolipids. Fatty aldehydes are particularly toxic molecules that can covalently react with proteins and certain amino-containing lipids such as phosphatidylethanolamine (PE), generating an unusual aldehyde adduct, N-alkyl-PE (NAPE). Using Faldh-deficient Chinese hamster ovary cells (FAA-K1A) as a cellular model for SLS, we investigated the ability of an aldehyde trapping agent, ADX-102 [2-(3-amino-6-chloro-quinolin-2-yl)-propan-2-ol], to mitigate the harmful effects of fatty aldehydes. FAA-K1A cells were protected from octadecanal (C18:0-al) induced cytotoxicity and apoptosis by ADX-102. Metabolism of C18:0-al to fatty alcohol (octadecanol) was also inhibited by ADX-102. FAA-K1A cells accumulated 5-fold more NAPE with C16- and C18-linked N-alkyl chains compared to wild-type cells, but NAPE levels decreased to normal after growth for 4 days with 50 µM ADX-102. Our results suggest that small aldehyde-reactive molecules, such as ADX-102, should be explored as novel therapeutic agents for SLS by preventing aldehyde adduct formation with critical cellular targets and inhibiting fatty aldehyde metabolism to fatty alcohol.

End-stage crystalline maculopathy with retinal atrophy in Sjögren-Larsson syndrome: a case report and review of the literature.

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive neurocutaneous disorder. It is caused by the inheritance of sequence variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). Universal signs of the condition are congenital ichthyosis, spastic paresis of the lower and upper limbs, and reduced intellectual ability. In addition to this clinical triad, patients with SLS experience dry eyes and decreased visual acuity caused by a progressive retinal degeneration. Examination of the retina in patients with SLS often reveals glistening yellow crystal-like deposits surrounding the fovea. This crystalline retinopathy often develops in childhood and is considered pathognomonic for the disease. The metabolic disorder typically shortens lifespan to half that of the unaffected population. However, now that patients with SLS live longer, it becomes increasingly important to understand the natural course of the disease. Our case describes a 58-year-old woman with advanced SLS whose ophthalmic examination illustrates the end-stage of the retinal degeneration. Optical coherence tomography (OCT) and fluorescein angiography confirm the disease is restricted to the neural retina with dramatic thinning of the macula. This case is unique since it is among the most advanced both in terms of chronological age and severity of retinal disease. While the accumulation of fatty aldehydes, alcohols, and other precursor molecules is the probable cause of retinal toxicity, a more complete understanding of the course of retinal degeneration may aid in the development of future treatments. The aim of our presentation of this case is to increase awareness of the disease and to foster interest in therapeutic research which may benefit patients with this rare condition.

Eye issues in Sjogren-Larsson Syndrome Sjögren-Larsson syndrome (SLS) is a rare, inherited condition that affects the skin and nervous system. It is caused by variations in a gene that controls the way fats are broken down in the body. The three key signs of the disease are (1) peeling, dry skin; (2) muscle stiffness and impaired movement of the arms and legs; and (3) reduced intellectual ability. Most signs of the condition appear shortly after birth. Genetic testing and counseling services can help patients and their families to understand what to expect with SLS. Caring for people with SLS requires teamwork by specialists like neurologists and physical therapists. Because eye problems are common, the early consultation of an eye doctor is also important. An eye examination can also confirm the diagnosis of SLS. SLS often causes the eyes to appear red, feel dry, or become irritated. This can make it hard to see in bright light. Decreased vision at night is also common. This is caused by the progressive loss of the central part of the retina which is needed to see fine details. Because SLS shortens lifespan, it is rare for anyone to reach the final stages of the disease. As patients with SLS are living longer, as illustrated by the individual in our case study, it becomes important to understand how the disease progresses. Unfortunately, treatments to restore vision are not yet available. Nevertheless, some protective measures can be taken. Eye examinations in early childhood are important for preventing damage to the eyes. Wearing glasses can improve vision, as well as protect eyes from accidental injury or falls. Eye drops can provide relief from dry eyes, and sunglasses can reduce glare and sensitivity to light. In the future, gene therapy may be used to treat SLS.

Impaired Skin Barrier Function Due to Reduced ω-O-Acylceramide Levels in a Mouse Model of Sjögren-Larsson Syndrome.

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.

Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.

Mutations in ALDH3A2 cause Sjögren-Larsson syndrome (SLS), a neuro-ichthyotic condition due to the deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro, and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of nonclassical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed five novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde-oxidizing activity was observed with cases-2 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing milia-like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder.

Muscle Tone Assessment under General Anesthesia for Sjögren-Larsson Syndrome and Spasticity.

INTRODUCTION: Study of muscle tone in individuals with severe spasticity (Modified Asworth Scale - MAS:3) under general anesthesia can confirm or rule out the eventual necessity of the impending spasticity relieving ablative neurosurgery by observing the hypertonia reduction and passive range of motion expansion. Therefore, what we measure under muscle relaxants is practically a fixed deformity. CASE PRESENTATION: The study was performed on a girl with Sjögren-Larsson syndrome, presenting with icthyosis and spastic diplegia. Proposed intervention was Dorsal Rhizotomy. Under general anesthesia, with and without muscle relaxants, hypertonia was significantly reduced (MAS:1), but the angle of motion did not increase much. CONCLUSION: We decided not to perform such a neurosurgical procedure. In ambiguous situations, the proposed study can help in decision-making for spasticity treatment.

Sjögren-Larsson syndrome: Anesthetic considerations and practical recommendations.

BACKGROUND: Sjögren-Larsson syndrome is a rare inherited neurocutaneous disorder characterized by congenital ichthyosis, spasticity, intellectual disability, seizures, and ophthalmologic changes. Most individuals with Sjögren-Larsson syndrome live well into adulthood and often require surgical intervention to manage their symptomatology. AIMS: The aim of this work was to review the clinical aspects of Sjögren-Larsson syndrome, highlight the unique anesthetic considerations associated with this disease, and provide practical recommendations about anesthetic management. METHODS: A retrospective case review from February 2013 to October 2019 was performed based on subject participation in a Sjögren-Larsson syndrome longitudinal study at the University of Nebraska Medical Center. Anesthetic and surgical records were reviewed for the following data: age, sex, relevant comorbid conditions, anesthetic induction and maintenance agents, intravenous and oral analgesics, muscle relaxants, and anesthetic-related complications. RESULTS: Fourteen patients with Sjögren-Larsson syndrome undergoing 48 anesthetic events were identified. A variety of anesthetic techniques was utilized. No serious adverse events were encountered. The most common clinical observations were related to the ichthyosis seen in Sjögren-Larsson syndrome, which led to difficulty in adherence of electrocardiogram leads and intravenous catheter dressings. CONCLUSIONS: We found that anesthesia can be safely administered in patients with Sjögren-Larsson syndrome. Providers should be aware of anesthetic management issues in Sjögren-Larsson syndrome including challenges placing and securing lines and monitors secondary to the ichthyosis.

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.

Comprehensive in silico screening and molecular dynamics studies of missense mutations in Sjogren-Larsson syndrome associated with the ALDH3A2 gene.

Sjögren-Larsson syndrome (SLS) is an autoimmune disorder inherited in an autosomal recessive pattern. To date, 80 missense mutations have been identified in association with the Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) gene causing SLS. Disruption of the function of ALDH3A2 leads to excessive accumulation of fat in the cells, which interferes with the normal function of protective membranes or materials that are necessary for the body to function normally. We retrieved 54 missense mutations in the ALDH3A2 from the OMIM, UniProt, dbSNP, and HGMD databases that are known to cause SLS. These mutations were examined with various in silico stability tools, which predicted that the mutations p.S308N and p.R423H that are located at the protein-protein interaction domains are the most destabilizing. Furthermore, to determine the atomistic-level differences within the protein-protein interactions owing to mutations, we performed macromolecular simulation (MMS) using GROMACS to validate the motion patterns and dynamic behavior of the biological system. We found that both mutations (p.S380N and p.R423H) had significant effects on the protein-protein interaction and disrupted the dimeric interactions. The computational pipeline provided in this study helps to elucidate the potential structural and functional differences between the ALDH3A2 native and mutant homodimeric proteins, and will pave the way for drug discovery against specific targets in the SLS patients.

Sjogren-Larsson Syndrome: Mechanisms and Management.

Sjogren Larsson syndrome (SLS) is a rare autosomal recessive inborn error of lipid metabolism due to mutations in the ALDH3A2 that result in a deficiency of fatty aldehyde dehydrogenase (FALDH). The syndrome has a high prevalence in Sweden where it was first described, but now known to occur worldwide. The classical triad of ichthyosis, mental retardation and spasticity characterizes clinical features. Preterm birth is common. "Glistening white dots" in the retina is a pathognomic clinical feature. Magnetic resonance imaging of the brain demonstrates leukoencephalopathy predominant in the periventricular region. Cerebral MR spectroscopy reveals a characteristic abnormal lipid peak at 1.3ppm and a small peak at 0.9ppm. The primary role of FALDH is oxidation of medium and long-chain aliphatic aldehydes derived from fatty alcohol, phytanic acid, ether glycerolipids and sphingolipids. The diagnosis is based on the typical phenotype, demonstration of the enzyme deficiency and presence of biallelic mutations in the ALDH3A2. The management of SLS largely remains symptomatic currently. However, several potential therapeutic options are being developed, keeping in view of the fundamental metabolic defects or correcting the genetic defect. This review aims to summarize the clinical, genetic and biochemical findings, pathogenetic mechanisms and the current therapeutic options, in SLS.

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.

Sjögren-Larsson syndrome: a complex metabolic disease with a distinctive ocular phenotype.

Purpose: Sjögren-Larsson Syndrome (SLS) is a rare genetic disorder characterized by a distinctive crystalline maculopathy, congenital ichthyosis, spasticity and intellectual disability. We review the genetic, biochemical and clinical aspects of SLS with a particular focus on the ophthalmologic features of the disease.Methods: Published reports of SLS are combined with clinical experience to provide an overview of this disease.Results: SLS is caused by bi-allelic mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase, a key enzyme needed for the metabolism of long-chain aliphatic aldehydes and alcohols. SLS patients display perifoveal crystalline inclusions (glistening white dots) that appear in early childhood, vary from sparse to florid and are located in the inner retina. Other findings include retinal thinning, cystic macular degeneration, retinal pigment epithelium atrophy and deficiency of macular pigment. Photophobia is common. Visual evoked potentials are often absent or delayed, whereas electroretinography studies are usually normal. Mild-moderate deficits in visual acuity are common but vision is usually preserved into adulthood. The maculopathy is thought to be due to the accumulation of fatty aldehydes and/or alcohols, which alter membrane function. Defective macular pigment metabolism may also contribute to a unique susceptibility to photo-oxidative damage in the retina.Conclusions: The distinctive retinal phenotype, together with the neurologic and cutaneous symptoms, allows the ophthalmologist to reliably diagnose SLS. Although no effective treatment exists for the ocular symptoms, emerging insight into the pathogenic mechanisms at play in the eye promises to bring effective therapy for SLS in the future.

Genetic assessment of ten Egyptian patients with Sjögren-Larsson syndrome: expanding the clinical spectrum and reporting a novel ALDH3A2 mutation.

Assessment of ten Egyptian patients with Sjögren-Larsson syndrome (SLS) detected; unusual clinical manifestations, a first report of brain atrophy in SLS, some patients exhibited neither retinal dots nor white matter changes previously reported as essential manifestations. We identified five mutations in ALDH3A2 gene including a novel one and suggest a founder effect. Sjögren-Larsson syndrome is a rare autosomal recessive inborn error of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase and result in a triad of ichthyosis, spasticity, and mental retardation. Clinical, radiological, biochemical, and neurophysiological evaluation in ten SLS patients descending from seven unrelated Egyptian pedigrees was followed by Sanger sequencing of ALDH3A2 performed by ABI 3500. All patients presented with SLS triad; ichthyosis, spasticity of four limbs and hyperreflexia with an intelligent quotient (IQ) ranging from (39 to 69). Other manifestations were dysmorphic features, seizures, and skeletal and ophthalmological affection. Mutational analysis of ALDH3A2 gene revealed three missense, one splice site, and one novel stop codon mutation; c.991G>T (p.E331X). Biochemical studies showed decrease of fatty aldehyde dehydrogenase activity. Our results reinforce the distinct clinical, radiological, and biochemical features of ALDH3A2-related SLS which are the clue for targeted molecular testing. Moreover, we present additional unreported clinical findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

Evaluation of corneal layers and anterior sclera in patients with primary Sjögren's syndrome / Avaliação das camadas da córnea e da esclera anterior na síndrome de Sjögren primária

ABSTRACT Purpose: We aimed to compare the thickness of anterior sclera, corneal layers, and pre-ocular tear film between patients with primary Sjögren's syndrome and healthy individuals. Methods: Fifty-one patients with primary Sjögren's syndrome and 41 healthy control participants were recruited in this cross-sectional and comparative study. The thickness of the pre-ocular tear film, corneal epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium were measured on the corneal apex. Anterior scleral thickness was measured at distances of 1 mm and 3 mm from the limbus. The anterior segment module of spectral-domain optical coherence tomography was used to measure thicknesses of pre-ocular tear film, corneal layers, and anterior sclera. Results: Tear film thickness, Schirmer's test, and tear break up time values were significantly lower in the Sjögren's disease group than in the healthy controls (p<0.05). The thickness measurements of corneal layers and sclera were similar between the groups. Tear film thickness was moderately correlated with the Schirmer's test results (r=0.34, p=0.001), but there was no correlation between the Schirmer's test results and tear break up time (r=0.18, p=0.09). Conclusions: Pre-ocular tear film, as measured by anterior segment optical coherence tomography, was thinner in patients with primary Sjögren's syndrome than in the healthy controls. The thicknesses of corneal layers and anterior sclera were similar between the groups.

RESUMO Propósito: Nosso objetivo foi comparar a espessura da esclera anterior, camadas da córnea e do filme lacrimal pré-ocular entre pacientes com síndrome de Sjögren primária e indivíduos saudáveis. Métodos: Cinquenta e um pacientes com síndrome de Sjögren primária e 41 controles saudáveis foram recrutados neste estudo comparativo e transversal. A espessura do filme lacrimal pré-ocular, epitélio corneal, camada de Bowman, estroma, membrana de Descemet e endotélio foram medidos no ápice corneal. A espessura da esclera anterior foi medida às distâncias de 1 mm e 3 mm do limbo. O módulo do segmento anterior da tomografia de coerência óptica de domínio espectral foi utilizado para mensurar as espessuras do filme lacrimal pré-ocular, camadas da córnea e esclera anterior. Resultados: A espessura do filme lacrimal, o teste de Schirmer e os valores do tempo de ruptura do filme lacrimal foram significativamente menores no grupo com síndrome de Sjögren do que nos controles saudáveis (p<0,05). As medidas de espessura das camadas corneais e da esclera foram similares entre os grupos. A espessura do filme lacrimal foi moderadamente correlacionada com os resultados do teste de Schirmer (r=0,34, p=0,001), mas não houve correlação entre os resultados do teste de Schirmer e tempo de ruptura (r=0,18, p=0,09). Conclusões: O filme lacrimal pré-ocular, medido pela tomografia de coerência óptica de segmento anterior, foi mais fino em pacientes com síndrome de Sjögren primária do que nos controles saudáveis. As espessuras das camadas da córnea e da esclera anterior foram semelhantes entre os grupos.

Genotype and phenotype variability in Sjögren-Larsson syndrome.

The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient-centered literature data was merged into a concise genotype-based, open-access database (www.LOVD.nl/ALDH3A2). One hundred and seventy eight individuals with 90 unique SLS-causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype-phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.