Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders Minzhi Xing, Emory University E I Parker, Emory University A Moreno-De-Luca, Geisinger Health System Elie Harmouche, Emory University Michael Terk, Emory University Journal Title: British Journal of Radiology Volume: Volume 87, Number 1033 Publisher: British Institute of Radiology | 2014-01-01, Pages 20130467-20130467 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1259/bjr.20130467 Permanent URL: https://pid.emory.edu/ark:/25593/pr2p5 Final published version: http://dx.doi.org/10.1259/bjr.20130467 Copyright information: © 2014 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact. Accessed September 24, 2021 3:09 PM EDT BJR © 2014 The Authors. Published by the British Institute of Radiology Received: Revised: Accepted: doi: 10.1259/bjr.20130467 28 July 2013 29 October 2013 8 November 2013 Cite this article as: Xing M, Parker EI, Moreno-De-Luca A, Harmouche E, Terk MR. Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders. Br J Radiol 2014;87:20130467. REVIEW ARTICLE Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders 1M XING, MD, 1E I PARKER, MD, 2A MORENO-DE-LUCA, MD, 1E HARMOUCHE, MD and 1M R TERK, MD 1Division of Musculoskeletal Imaging, Department of Radiology and Imaging Sciences, Emory University Hospital, Atlanta, GA, USA 2Department of Radiology, Geisinger Autism & Developmental Medicine Institute, the Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA Address correspondence to: Dr Minzhi Xing E-mail: [email protected] The scientific abstract “Multimodality imaging of the lysosomal storage diseases part I: the non-lipids” was presented at the 2011 Radiological Society of North America (RSNA) Annual Scientific Meeting. ABSTRACT Lysosomal storage diseases (LSDs) are a large group of genetic metabolic disorders that result in the accumulation of abnormal material, such as mucopolysaccharides, glycoproteins, amino acids and lipids, within cells. Since many LSDs manifest during infancy or early childhood, with potentially devastating consequences if left untreated, timely identification is imperative to prevent irreversible damage and early death. In this review, the key imaging features of the non-lipid or extralipid LSDs are examined and correlated with salient clinical manifestations and genetic information. Disorders are stratified based on the type of excess material causing tissue or organ dysfunction, with descriptions of the mucopolysaccharidoses, mucolipidoses, alpha-mannosidosis, glycogen storage disorder II and cystinosis. In addition, similarities and differences in radiological findings between each of these LSDs are highlighted to facilitate further recognition. Given the rare and extensive nature of the LSDs, mastery of their multiple clinical and radiological traits may seem challenging. However, an understanding of the distinguishing imaging characteristics of LSDs and their clinical correlates may allow radiologists to play a key role in the early diagnosis of these progressive and potentially fatal disorders. Lysosomal storage diseases (LSDs) are genetic disorders substances, including mucopolysaccharides, glycoproteins, that cause metabolic pathway deficiencies and abnormal glycogen and amino acids. accumulation of material within the lysosome, leading to excess storage of substances, such as mucopolysaccharides, Mucopolysaccharidoses glycoproteins, amino acids and lipids.1 Although the LSDs The mucopolysaccharidoses (MPSs) are a group of LSDs encompass a large group of approximately 50 rare inherited resulting from a deficiency in enzymes that degrade gly- metabolic disorders, certain similarities and differences may cosaminoglycans (GAGs) (mucopolysaccharides). There be appreciated between the LSDs based on the type of enzyme are seven distinct MPSs—MPS I: Hurler syndrome, MPS deficiency, the type of abnormal substrate that accumulates II: Hunter syndrome, MPS III: Sanfilippo syndrome, MPS and the specific tissue or organs most affected.1 Many LSDs IV: Morquio syndrome, MPS VI: Maroteaux–Lamy syn- manifest during infancy or early childhood and may have drome, MPS VII: Sly syndrome and MPS IX: Natowicz devastating consequences if untreated, including early death.1 syndrome. MPS V and VIII are no longer used as disease Therefore, early recognition is imperative given the avail- designations.2 Genetic mutations and clinical and radiolog- ability of new treatment options to prevent irreversible ical manifestations of the MPSs are summarized in Table 1. damage.1 Radiologists may benefit from understanding the characteristic clinical and imaging features of the LSDs, Mucopolysaccharidosis I: Hurler syndrome including the similarities and differences, and can assist the MPS I or Hurler syndrome is due to a-L-iduronidase de- clinician with both diagnosis and prognosis. This article ficiency, resulting in the abnormal accumulation of GAGs discusses the clinical and imaging features of those LSDs dermatan sulfate and heparan sulfate in the cell.7 MPS I has that involve abnormal accumulation of non-lipid or extralipid an autosomal recessive inheritance pattern.8 The incidence 2of14 Table 1. Summary of clinical and radiological manifestations of the mucopolysaccharidoses (glycosaminoglycan storage disorders) BJR Gene Clinical and radiological characteristics Mucopolysac- Incidence Accumulated bjr.birjournals.org mutation Deficient charidoses: per 100 000 glycosamino- and locus enzyme eponym live births3 glycans Cardiac Respiratory Musculoskeletal Neurological Developmental (inheritance)2,4 Dysostosis multiplex, including thoracolumbar Brain atrophy, gibbus, oar-shaped thickened meninges, ribs, thickened Cardiomyopathy, patchy white matter Speech delay, Airway narrowing, clavicles, coxa valga, MPS I: Hurler IDUA 4p16.3 Dermatan sulfate, valvular disease, changes, multiple subsequent 0.11–1.67 a-L-iduronidase recurrent respiratory J-shaped sella turcica, syndrome (AR) heparan sulfate myocardial perivascular spaces, cognitive, visual and infections, OSA genu valgum, ischaemia, CHF hydrocephalus, auditory decline abnormal dens, cervical cord thickened ligaments compression and atlantoaxial subluxation leading to cord compression Similar to MPS I, Severe form: loss of Dysostosis multiplex severe form: MPS II: Hunter Iduronate-2- Dermatan sulfate, cognitive function, 0.10–1.07 IDS Xq28 (XR) Severe form—similar to MPS I with similar features seizures, syndrome sulfatase heparan sulfate death in first or to MPS I psychomotor second decade retardation IIIA: heparan-N- IIIA: SGSH, sulfatase; IIIB: a-N- Normal development 17q25.3; IIIB: acetylglucosaminidase; Dysostosis multiplex Similar features to until 2–6 years old. MPS III: Sanfilippo NAGLU, 17q21; IIIC: acetyl-CoA a- with similar features 0.29–1.89 Heparan sulfate Similar to MPS I MPS I, but may be Subsequent rapid syndrome IIIC: HGSNAT, glucosaminide to MPS I, but may be more extensive neurological 8p11.1; IIID: acetyltransferase; IIID: mild deterioration GNS, 12q14 (AR) N-acetylglucosamine 6-sulfatase IVA: GALNS, Dysostosis multiplex IVA: Similar to MPS I, MPS IV: Morquio 16q24.3; IVB: Keratan sulfate, with similar features Typically normal 0.15–1.31 galactose-6-sulfatase; severe valvular Similar to MPS I Similar to MPS I syndrome GLB1, 3p21.33 chondroitin sulfate to MPS I, but often intelligence IVB: b-galactosidase disease4 (AR) severe MPS VI: Dysostosis multiplex ARSB 5q11–q13 Dermatan sulfate, Typically normal Maroteaux–Lamy 0.14–0.38 Arylsulfatase-b Similar to MPS I with similar features Similar to MPS I (AR) chondroitin sulfate intelligence syndrome to MPS I Ranges from fatal Dermatan sulfate, non-immune heparan sulfate, Dysostosis multiplex hydrops fetalis in MPS VII: Sly chondroitin 0.02–0.29 GUSB 7q21.11 (AR) b-glucuronidase Similar to MPS I with similar features Similar to MPS I severe form to syndrome 4-sulfate, Br J Radiol;87:20130467 to MPS I normal growth and chondroitin mental development 6-sulfate in mildest form AR, autosomal recessive; ARSB, Arylsulfatase-b; CHF, congestive heart failure; CoA, coenzyme A; GALNS, Galactosamine (N-acetyl)-6-sulfate sulfatase; GLB1, b1-galactosidase; GNS, N-acetylglucosamine-6-sulfatase; GUSB, b-glucuronidase; HGSNAT, Heparan-a-glucosaminide N-acetyltransferase; IDS, Iduronate 2-sulfatase; IDUA, a-L-iduronidase; MPS, mucopolysaccharidosis; NAGLU, a-N-acetylglucosaminidas; OSA, obstructive sleep apnoea; SGSH, N-sulfoglucosamine sulfohydrolase; XR, X-linked recessive. M Xing Spectrum of radiographic manifestations of dysostosis dultiplex includes upper limb deformities, flaring of the iliac wings and hip dysplasia. The terms MPS V and MPS VIII are no longer used as disease designations.2 MPS IX (Natowicz syndrome) is due to a deficiency in hyaluronidase, with four cases having been described in the literature.5,6 et al Review article: Radiological features of non-lipid lysosomal storage diseases BJR Figure 1. Dysostosis multiplex in a young child with mucopo- multiplex is the term used