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Highlights on Genomics Applications for Lysosomal Storage Diseases

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Highlights on Genomics Applications for Lysosomal Storage Diseases cells Review Highlights on Genomics Applications for Lysosomal Storage Diseases Valentina La Cognata 1, Maria Guarnaccia 1, Agata Polizzi 2, Martino Ruggieri 3 and Sebastiano Cavallaro 1,* 1 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, Italy; [email protected] (V.L.C.); [email protected] (M.G.) 2 Chair of Pediatrics, Department of Educational Sciences, University of Catania, Via Casa Nutrizione, 39, 95124 Catania, Italy; [email protected] 3 Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, AOU “Policlinico”, PO “G. Rodolico”, Via S. Sofia, 78, 95123 Catania, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-095-7338128 Received: 15 July 2020; Accepted: 11 August 2020; Published: 14 August 2020 Abstract: Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem genetic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the lysosome. Although the cellular pathogenesis of LSDs is complex and still not fully understood, the approval of disease-specific therapies and the rapid emergence of novel diagnostic methods led to the implementation of extensive national newborn screening (NBS) programs in several countries. In the near future, this will help the development of standardized workflows aimed to more timely diagnose these conditions. Hereby, we report an overview of LSD diagnostic process and treatment strategies, provide an update on the worldwide NBS programs, and discuss the opportunities and challenges arising from genomics applications in screening, diagnosis, and research. Keywords: lysosomal storage diseases; diagnosis; genomics; newborn screening 1. Introduction Lysosomal storage diseases (LSDs) are a heterogeneous group of heritable (inborn) metabolism defects that affect the function of lysosomes. This group comprises about 70 monogenic disorders of lysosomal catabolism and is characterized by a gradual accumulation of non-degraded substrates inside the lysosome, which in turn leads to cellular dysfunction, tissue damage, and death [1]. The majority of LSDs are inherited as autosomal recessive traits (except for Fabry, Hunter, and Danon diseases that are X- linked) and are caused by mutations in genes encoding lysosomal proteins (i.e., acidic hydrolases, integral membrane proteins, and activator or carrier proteins) whose functional deficiencies trigger the pathogenetic cascade [2]. Although each disorder is rare, per se, with estimated incidences ranging from 1 in 50,000 to 1 in 250,000 live births, LSDs as a group are relatively common disorders (1:5000 live births) [1]. LSDs can be categorized by (a) the biochemical type of stored material (e.g., sphingolipidoses, mucopolysaccharidoses, glycoproteinoses); (b) the post-translational modification of lipofuscin degradation or metabolism defects; (c) the dysfunctions in membrane proteins; or (d) the altered lysosome-related organelle (LRO) defects (Figure1). Clinically, LSDs may present with a broad range of phenotypes reflecting the age of onset (e.g., more severe infantile forms vs. later/adult milder forms) [3], the extent and severity of nervous system Cells 2020, 9, 1902; doi:10.3390/cells9081902 www.mdpi.com/journal/cells CellsCells2020 2020, 9, ,9 1902, x FOR PEER REVIEW 2 of2 of15 15 system and/or systemic involvements, and the related variability of signs and/or symptoms. In andgeneral,/or systemic the disease involvements, progresses and evolves the related relent variabilitylessly over of time. signs Signs and /anord/or symptoms. symptoms In mainly general, theinclude disease facial progresses dimorphisms, and evolves psychomotor relentlessly developmental over time. Signsdelay andand/ orcognitive symptoms decline, mainly seizures, include facialimpairment dimorphisms, of vision, psychomotor recurrent developmentalinfections, musc delayle deficits, and cognitive organomegaly, decline, seizures,immune impairmentdefects, and of vision,skeletal recurrent changes, infections, all having muscle a severe deficits, impact organomegaly, on prognosis immune and influencing defects, and the skeletalquality changes,of life for all havingpatients a severeand families impact [4,5]. on prognosis and influencing the quality of life for patients and families [4,5]. FigureFigure 1. 1.Disorders Disorders ofof lysosomeslysosomes and lysosome-related organelles organelles (LROs). (LROs). Lysosomal Lysosomal storage storage diseases diseases (LSDs)(LSDs) and and LROsLROs havehave beenbeen subclassifiedsubclassified accordingaccording to to the the biochemical biochemical type type of of stored stored material material (sphingolipidoses,(sphingolipidoses, mucopolysaccharidoses, mucopolysaccharidoses, glycoproteinoses,glycoproteinoses, lipid storage storage diseases) diseases) or or to to the the integral integral membranemembrane proteins, proteins, post-translational post-translational modification, modification, and lipofuscinand lipofuscin metabolism metabolism defects. defects. The causative The genecausative is specified gene is in specified parentheses. in parentheses. 2.2. The The Biology Biology ofof LysosomesLysosomes LysosomesLysosomes areare thethe keykey cellularcellular organellesorganelles in macromolecule catabolism, catabolism, responsible responsible for for the the breakdownbreakdown andand recyclingrecycling ofof aa widewide rangerange of complex metabolites including including glycosides, glycosides, lipids, lipids, phospholipids,phospholipids, proteins, proteins, andand nucleicnucleic acids.acids. This catabolic function function is is orchestrated orchestrated by by approximately approximately 6060 unique unique acidicacidic hydrolase hydrolase enzymes enzymes (glycosidases, (glycosidases, sulfatases, sulfatases, peptidases, peptidases, phosphatases, phosphatases, lipases, lipases, and andnucleases), nucleases), which which are arelocated located within within the the lysosomal lysosomal lumen lumen where where the the enzyme enzyme and and the the substrate substrate interactinteract with with each each other. other. While While the enzymesthe enzymes are mainly are mainly synthesized synthesized within thewithin endoplasmic the endoplasmic reticulum (ER),reticulum tagged (ER), with tagged a mannose-6-phosphate with a mannose-6-phosphate (M6P) residue (M6P) in residue the Golgi in the apparatus Golgi apparatus and then and traffi thencked intotrafficked the lysosome into the [6 lysosome,7], the substrates [6,7], the are substrates transported are transported through diff througherent routes different according routes to according the nature ofto the the cargo. nature Materialsof the cargo. from Materials outside from the cell outs areide delivered the cell are through delivered the through endocytosis the endocytosis pathway via clathrin-mediatedpathway via clathrin-mediated or caveolin-mediated or caveolin-mediated endocytosis vesicles. endocytosis The cell’s vesicles. own macromolecules The cell’s own and metabolitesmacromolecules are processed and metabolites and degraded are processed through autophagy,and degraded in one through of its functionalautophagy, forms in one including of its macroautophagy,functional forms microautophagy,including macroautophagy, and chaperone-mediated microautophagy, autophagy and chaperone-mediated [8]. Recent evidence autophagy shows that[8]. lysosomesRecent evidence are not shows only catabolicthat lysosomes organelles, are not but only they catabolic also function organelles, as metabolic but they also hubs function controlling as nutrientmetabolic sensing, hubs controlling amino-acid nutrient and ion sensing, homeostasis, amino-acid vesicle and tra ionffi cking,homeostasis, and cellular vesicle growth, trafficking, and and they establishcellular contactgrowth, sitesand withthey otherestablish organelles contact (e.g., sites mitochondria,with other organelles ER, or peroxisomes) (e.g., mitochondria, [7,9]. ER, or peroxisomes) [7,9]. 3. Diagnosis and Therapeutic Strategies 3. Diagnosis and Therapeutic Strategies Diagnosis of LSDs is often a challenge for clinicians, owing to the rarity of single disorders and to the non-specificityDiagnosis of LSDs of signs is often and/ ora challenge symptoms, for oftenclinicians, attributed owing to to other the rarity neurological of single and disorders/or systemic and diseases.to the non-specificity Before the spread of signs of expanded and/or newbornsymptoms, screening, often attributed individuals to other were diagnosedneurological years and/or after signsystemic and/or diseases. symptom Before onset, the when spread the of disease expanded was newborn already advancedscreening, and indi interventionsviduals were diagnosed proved less efficacious [10]. Cells 2020, 9, x FOR PEER REVIEW 3 of 15 Cellsyears2020 ,after9, 1902 sign and/or symptom onset, when the disease was already advanced and interventions3 of 15 proved less efficacious [10]. The typical diagnostic work-up for LSDs includes taking a detailed history on the clinical The typical diagnostic work-up for LSDs includes taking a detailed history on the clinical presentation(s) and course of disease; measuring the activity of single enzymes or protein abundance presentation(s) and course of disease; measuring the activity of single enzymes or protein abundance in in leukocytes, fibroblasts, urine, or rehydrated
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