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,

rJRadiol;87:20130467 J Br 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. Xing M 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 tal et 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 to describe progressive skeletal dys- 4,9 lysaccharidosis I (Hurler syndrome). Sagittal T1 MR image of plasia seen in MPS I and other MPSs. The skeletal dysplasia the lumbar spine demonstrates lumbar gibbus centred at L1 results from a lack of skeletal remodelling and ossification ab- with hypoplasia (black arrow), anterior beaking (black arrow- normalities owing to abnormal deposition of GAGs in bone and head) and posterior scalloping (white arrowheads). Lumbar cartilage.8 GAGs also accumulate in tendons, ligaments and joint gibbus is characterized by angular deformity of the spine due capsules, and patients may develop joint contractures.8 Radio- to vertebral hypoplasia or wedging, commonly seen with graphic manifestations of dysostosis multiplex include thoraco- dysostosis multiplex. lumbar gibbus deformity because of vertebral body wedge deformity or hypoplasia (Figure 1), oar-shaped ribs and thickened clavicles (Figure 2a), flaring of the iliac wings, hip dysplasia and coxa valga (Figure 2b), along with numerous other osseous dys- plasias detailed later in this article.4,8,9

Cardiovascular abnormalities observed in MPS I because of GAG infiltration of cardiac tissue include valvular disease, endo- cardial fibroelastosis, arrhythmias, congestive heart failure, aortic – stenosis and myocardial ischaemia.10 14 In addition, patients with MPS I may suffer from respiratory infections and obstructive sleep apnoea, with GAGs infiltrating into airway soft tissues, cartilage and the thoracic cage.13,15

GAGs may also accumulate in the central nervous system (CNS), including within the meninges and even adjacent bone.13 Indi- viduals with the severe form of MPS I may have developmental delay, particularly speech delay, which is then followed by a de- cline in cognitive, visual and auditory function.13 Other CNS manifestations as a result of abnormal GAG accumulation include brain atrophy, thickened meninges, prominent subarachnoid spaces, patchy white matter signal abnormality, multiple peri- – vascular spaces and hydrocephalus (Figure 2c).13,16 18 Addi- tionally, cervical cord compression from a dysplastic or hypoplastic dens, thickened or abnormal ligaments (Figures 2d and 3)and atlantoaxial subluxation may also occur.13,16,17

Other clinical features of MPS I include coarse facial features, microcephaly, hearing loss, corneal clouding, hepatosplenomegaly, thickened skin and inguinal hernias.4,13

Mucopolysaccharidosis II: Hunter syndrome MPS II or Hunter syndrome is due to iduronate sulfatase de- ficiency resulting in the accumulation of dermatan sulfate and heparan sulfate within the cell. MPS II has an X-linked recessive inheritance pattern.19 The incidence of MPS II ranges from 0.10/ 100 000 to 1.07/100 000 live births depending on the country reviewed.3 MPS II may be further differentiated into severe and attenuated forms.19 In the attenuated form, patients typically of MPS I ranges from 0.11/100 000 to 1.67/100 000 live births, live into early adult years and have little to no CNS involvement. with incidence variation depending on the country reviewed.3 By contrast, there is progressive loss of cognitive function and MPS I has traditionally been categorized into Hurler syn- early death typically in the first or the second decade of life in drome, Hurler–Scheie syndrome and Scheie syndrome.7 How- the severe form.19 Patients with the severe form may exhibit ever, biochemical differences have not been identified between upper respiratory airway narrowing and cardiac valve abnor- these categories.7 Therefore, MPS I is best classified into severe malities.19 or attenuated forms, a difference which influences therapeutic options.7 In the severe form, early onset of clinical symptoms There are many clinical similarities between MPS II and pre- and earlier death owing to complications (usually in the first viously discussed MPS I (Hurler syndrome), including dysostosis decade) are common distinctions from the attenuated form.7 multiplex.4,8,11,20 Additional examples of skeletal manifestations seen in dysostosis multiplex other than those previously discussed Clinical and radiographic features of MPS I are frequently ob- under MPS I include genu valgum, widening of the diaphysis of served in the other MPSs, as well as in other LSDs. Dysostosis long bones, hypoplastic distal ulna and tilted radius, varus deformity

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Figure 2. (a) Dysostosis multiplex in an adolescent patient with mucopolysaccharidosis I (Hurler syndrome). Frontal chest radiograph demonstrates oar-shaped ribs (black arrows) and thickened clavicles (white arrowheads) commonly seen in dysostosis multiplex. Further images of the same patient are seen in (b)–(d). (b) Dysostosis multiplex. Frontal radiograph of the pelvis demonstrates an abnormally formed pelvis with rounded or flared iliac wings (white arrow) and double contour iliac walls (black arrow). Additionally, there is hip dysplasia (white arrowhead) and coxa valga deformity (black arrowhead). (c) Central nervous system changes. Axial T2 MR image of the brain demonstrates enlarged ventricles consistent with hydrocephalus. (d) Cervical cord compression (arrow) and dysplasia of the dens (arrowhead) on sagittal T2 weighted MRI.

of the proximal humerus (Figure 4a), pointed thick and short country reviewed.3 The clinical features seen in MPS III are also metacarpals, small and irregular carpal bones, thickened cal- similar to the features described in MPS I, with a few exceptions. varium and a J-shaped sella turcica (Figure 4b).4,8,9 In contrast MPS III may have milder dysostosis multiplex than MPS I.22 to MPS I, seizures and severe psychomotor retardation are more However, MPS III may exhibit more extensive CNS abnormalities common in the severe form of MPS II.4 Overall, the CNS im- than the other MPSs. There is often normal neurological de- aging features may be similar between MPS I and II, including velopment until 2–6 years old, which is followed by rapid neu- extensive dilated perivascular spaces or cribriform changes rological deterioration.23 Findings from CNS imaging are similar (Figure 4c).17,21 to those for MPS I and II, including diffuse or patchy white matter changes and brain atrophy (Figure 5).17,21 Mucopolysaccharidosis III: Sanfilippo syndrome MPS III or Sanfilippo syndrome is due to an abnormal accu- Mucopolysaccharidosis IV: Morquio syndrome mulation of heparan sulfate within the cell. MPS III is divided MPS IV or Morquio syndrome has two subtypes from different into the following four subtypes based on the different enzyme enzymatic deficiencies, with MPS IVA being deficient in galactose- deficiencies: (1) MPS IIIA (heparan-N-sulfatase), (2) MPS IIIB 6-sulfatase and MPS IVB having a b-galactosidase deficiency and (a-N-acetylglucosaminidase), (3) MPS IIIC (acetyl-coenzyme less severe clinical features.2 MPS IV is caused by abnormal ker- A: a-glucosaminide acetyltransferase) and (4) MPS IIID atan sulfate and chondroitin sulfate accumulation in cells. This (N-acetylglucosamine-6-sulfatase).2 The incidence of MPS III disorder exhibits autosomal recessive inheritance, with an in- or Sanfilippo syndrome ranges from 0.29/100 000 to 1.89/100 000 cidence ranging from 0.15/100 000 to 1.31/100 000 live births live births, with variation of incidence reported depending on the depending on the country reviewed.3 Clinical features are similar

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Figure 3. Cervical cord compression due to abnormally thickened Mucopolysaccharidosis VI: ligaments (arrowhead) in a patient with mucopolysaccharidosis I Maroteaux–Lamy syndrome (Hurler syndrome) on sagittal T1 weighted MRI of the cervical spine. MPS VI or Maroteaux–Lamy syndrome is caused by arylsul- fatase-b deficiency, with abnormal accumulation of dermatan sulfate and chondroitin sulfate in cells.2 This disorder has an autosomal recessive inheritance pattern, with an incidence ranging from 0.14/100 000 to 0.38/100 000 live births depending on the country reviewed.3 Patients exhibit a spectrum of phe- notypic severity, with many clinical features similar to MPS I and the other MPSs, including dysostosis multiplex (Figure 7).4,26 However, individuals with MPS VI are typically intellectually normal.26

Mucopolysaccharidosis VII: Sly syndrome MPS VII or Sly syndrome results from a b-glucuronidase de- ficiency with dermatan sulfate, heparan sulfate, chondroitin-4- sulfate and chondroitin-6-sulfate accumulating abnormally in cells.27 MPS VII has an autosomal recessive inheritance pattern with an incidence ranging from 0.02/100 000 to 0.29/100 000 live births in the countries reviewed.3 The phenotype varies from a severe form presenting as fatal non-immune hydrops fetalis to a milder form with features similar to MPS I (including hepatosplenomegaly and recurrent respiratory infections).27,28 The least affected phenotype presents in the second decade of life with mild coarse facies and normal growth and mental de- velopment.27,28 Patients with MPS VII may have similar cardiac manifestations to other MPSs, with the abnormal accumulation of GAGs in cardiac tissue leading to complications of aortic – valve stenosis, as seen in Figure 8.10 13 As with the other MPSs, the musculoskeletal manifestations in MPS VII include dysos- tosis multiplex.27,28 to MPS I or Hurler syndrome, including dysostosis multiplex, Glycoprotein storage disorders which is often severe (Figure 6a).24 Dens and ligamentous ab- There are several LSDs that occur because of a deficiency in normalities may also occur, with complications including cord enzymes that either degrade glycoproteins or phosphorylate compression and atlantoaxial subluxation (Figure 6b).16,24,25 glycoproteins. Mucolipidosis I, mucolipidosis II, mucolipi- Other similar clinical features to MPS I include cardiac valve dosis III and alpha-mannosidosis are disorders included abnormalities and obstructive respiratory disease.4,12 However, within this group of LSDs. Genetic, clinical and radiological MPS IV patients typically exhibit normal intelligence and a lon- features of the glycoprotein storage disorders are summarized ger life span than those with MPS I.4,24 in Table 2.

Figure 4. (a) Dysostosis multiplex in a young child with mucopolysaccharidosis II (Hunter syndrome). Radiograph of the right (R) humerus demonstrates a widened diaphysis (arrow) and varus deformity of the proximal humerus (arrowhead). (b) Dysostosis multiplex: enlarged image of a J-shaped sella turcica (arrow) from a lateral radiograph of the skull. (c) Central nervous system changes. Axial T2 weighted MR image of the brain demonstrates extensive dilated perivascular spaces or cribriform changes.

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Figure 5. Central nervous system changes in an adolescent vision and ataxia.32,33 Patients with Type 1 lack the somatic 32 patient with mucopolysaccharidosis III (Sanfilippo syndrome). T2 changes commonly seen in Type 2. weighted MR image of the brain demonstrates brain atrophy. Type 2 mucolipidosis I includes congenital, infantile and ju- venile forms.34 The congenital form is associated with non- immune hydrops fetalis and ascites.33,34 The infantile form may have similar features to MPS I, including dysostosis multiplex (Figure 9), coarse facies, visceromegaly and develop- mental delay, but may develop macular cherry red spots in con- – trast to MPS I.32 34

Mucolipidosis II: I-cell disease Mucolipidosis II or I-cell disease is caused by a mutation in the N-acetylglucosamine-1-phoshate transferase, a/b subunits (GNPTAB) gene. This causes a deficiency in N-acetylglucosamine-1 phos- photransferase, which results in lysosomal acid hydrolase enzymes lacking a normal recognition phosphate group and abnormally accumulating in the extracellular space rather than the lysosome.35 Mucolipidosis II has autosomal recessive inheritance, with a world- wide prevalence of 0.15/100 000live births.29 Patients with mucoli- pidosis II usually have a short lifespan, commonly resulting in death – in early childhood because of cardiorespiratory problems.35 37 Cardiorespiratory abnormalities are similar to those seen in MPS I (Hurler syndrome), including cardiac valve problems, thickening of the airways and thoracic cage stiffening.35

Mucolipidosis I: sialidosis syndrome Other clinical similarities between mucolipidosis II and MPS I Mucolipidosis I or sialidosis is due to lysosomal a-N- may include dysostosis multiplex (Figure 10), short stature and acetylneuraminidase deficiency resulting in abnormal accumula- coarse facies.35,37 Compared with MPS I, dysostosis multiplex tion of sialic acid-containing oligosaccharides.32 Mucolipidosis I has been described to occur in a later phase of osseous changes has an autosomal recessive inheritance pattern and an incidence of in patients with mucolipidosis II, with the early phase of bone 0.02/100 000 live births.29 There are two subtypes, with Type 1 changes in these patients resembling rickets or hyperpara- manifesting during childhood or juvenile ages.33 Individuals with thyroidism seen in the neonatal period.35,37 Craniosynostosis, Type 1, also known as cherry red spot myoclonus syndrome, have premature closure of sutures that is often sporadic, has been macular cherry red spots, myoclonic epilepsy, progressive loss of reported in patients with mucolipidosis II (Figure 11).36,37

Figure 6. (a) Dysostosis multiplex in a young child with mucopolysaccharidosis IV (Morquio syndrome). Saggital T1 weighted MR image of the thoracic and lumbar spine demonstrates anterior beaking at the level of the middle vertebral body (arrowhead) and flattening of the vertebra (arrow). (b) Dysostosis multiplex: sagittal CT image of the cervical spine demonstrates hypoplastic dens (arrowhead) and atlantoaxial subluxation (arrows). Cervical cord compression was confirmed on MRI owing to the anterior subluxation of the posterior arch of C1.

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Figure 7. Dysostosis multiplex in a young child with mucopo- Figure 8. Valvulopathy in a child with mucopolysaccharidosis lysaccharidosis VI (Maroteaux–Lamy syndrome). Lateral radio- VII (Sly syndrome). Cardiac MRI reveals aortic valve stenosis graph of the thoracolumbar spine demonstrates inferior beaking (arrow) secondary to thickening of the valve from an abnormal of several vertebral bodies (arrows). This is in contrast to the build-up of glycosaminoglycans. mid-vertebral body beaking observed in Figure 6a.

than mucolipidosis II.38 Mucolipidosis III has an autosomal re- cessive inheritance pattern, with a prevalence that is probably similar to that in mucolipidosis II.38 In contrast to mucolipidosis II, clinical manifestations in mucolipidosis III alpha/beta typically occur around the age of 3 years, with death often occurring early in middle adulthood commonly caused by cardiorespiratory problems.38 Dysostosis multiplex (Figure 12), coarse facial fea- tures and short stature are also features of mucolipidosis III alpha/ beta but are often milder than in mucolipidosis II.38

Alpha-mannosidosis Alpha-mannosidosis results from a deficiency in lysosomal alpha- mannosidase enzyme, with mannose-rich oligosaccharides ac- cumulating abnormally.39 This disorder has an autosomal re- cessive inheritance pattern and is extremely rare with incidences reported from 0.20/100 000 to 0.33/100 000 live births depending on location.30 Clinical manifestations of alpha-mannosidosis include intellectual disability, coarse facial features and skeletal abnormalities of dysostosis multiplex (Figure 13), which are similar to the characteristics manifested in MPS I.30 In addition, immu- nodeficiencies and ataxia may be observed in patients with alpha- mannosidosis.30

Three clinical subtypes of alpha-mannosidosis have been sug- Individuals with mucolipidosis II may have more extensive gested: severe, moderate and mild forms.39 The severe form delay in motor development than intellectual impairment.36,37 manifests early and produces skeletal abnormalities, including dysostosis multiplex.30 Patients with the severe form typically die Mucolipidosis III: pseudo-Hurler polydystrophy from infection, primary CNS involvement or metabolic myopa- Mucolipidosis III alpha/beta or pseudo-Hurler polydystrophy thy early in life.30 The moderate form manifests before 10 years syndrome is also caused by N-acetylglucosamine-1-phospho- old with milder or slower progression of clinical features, in- transferase deficiency, with precursor lysosomal acid hydrolase cluding metabolic myopathy and ataxia.30 Patients with the enzymes accumulating in the extracellular space because of lack moderate form also have dysostosis multiplex, in contrast to the of a phosphate group as in I-cell disease.38 However, mucolipi- mild form that typically lacks skeletal abnormalities.30 Addi- dosis III is a milder and more attenuated form with the mutation tionally, the mild form has an onset later in life with slower of the GNPTAB gene resulting in more normal enzyme activity progression.30 Neuroimaging features reported in a few

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Table 2. Summary of clinical and radiological manifestations of the mucolipidoses (glycoprotein storage disorders) BJR

Glycoprotein Incidence Gene Clinical and radiological characteristics bjr.birjournals.org storage per 100 000 mutation Deficient Accumulated Cardio- disorders: live and locus enzyme substance Gastrointestinal Musculoskeletal Neurological Developmental eponym births29,30 (inheritance)31 respiratory

Type 1: myoclonic Type 2: ranges epilepsy, from non-immune Type 2: dysostosis Sialic progressive ataxia, hydrops fetalis in Mucolipidosis I: NEU1 6p21.3 a-N- Type 2: ascites, multiplex with 0.02 acid-containing None macular cherry congenital form to sialidosis syndrome (AR) acetylneuraminidase visceromegaly similar features to oligosaccharides red spots (may developmental MPS I also occur in delay in infantile Type 2) form

Early phase Delayed speech (neonatal): rickets or development, hyperparathyroidism, Lysosomal acid Motor deficits delayed motor Similar to MPS I, late Mucolipidosis II: GNPTAB N-acetylglucosamine-1- hydrolase enzymes Umbilical and secondary to development, 0.15 especially valvular phases: dysostosis I-cell disease 12q23.2 (AR) phosphotransferase in extracellular inguinal hernias bony which is more disease multiplex with space abnormalities extensive similar features to than intellectual MPS I, impairment craniosynostosis

N-acetylglucosamine-1- Similar to Dysostosis Mucolipidosis III Lysosomal acid phosphotransferase mucolipidosis II Similar to multiplex with alpha/beta: GNPTAB hydrolase enzymes 0.25–1.00 (more normal and MPS I, but may mucolipidosis II similar features to Similar to mucolipidosis II, but often milder pseudo-Hurler 12q23.2 (AR) in extracellular enzyme than in be milder/later (milder) MPS I, but often polydystrophy space mucolipidosis II) onset milder

Dysostosis multiplex with Cerebellar atrophy, similar features to white matter signal Respiratory MPS I in the abnormality, MAN2B1 infections, and Intellectual disability, Alpha- Mannose-rich severe and progressive 0.20–0.33 19cen–q13.1 Alpha-mannosidase other types of Visceromegaly motor mannosidosis oligosaccharides moderate forms of cortico-subcortical (AR) infections due to developmental delay alpha- atrophy, enlarged immunodeficiencies mannosidosis, or empty sella, metabolic ataxia myopathy

AR, autosomal recessive; GNPTAB, N-acetylglucosamine-1-phosphate transferase, a/b subunits; MAN2B1, Mannosidase, alpha, class 2B, member 1; MPS, mucopolysaccharidosis; NEU1, Neuraminidase-1. Spectrum of radiographic manifestations of dysostosis multiplex is similar to that seen in the mucopolysaccharidoses. rJRadiol;87:20130467 J Br Xing M tal et Review article: Radiological features of non-lipid lysosomal storage diseases BJR

Figure 9. Dysostosis multiplex in an infant with mucolipidosis I Figure 11. Craniosyntosis in an infant with mucolipidosis II (I-cell (sialidosis). Enlarged image of the left lower ribs demonstrates disease). Reformatted CT demonstrates premature closure of subtle broadening of the rib (arrowheads). the frontal (metopic) suture (black arrowhead) and right coronal suture (white arrowhead).

patients with alpha-mannosidosis include cerebellar atrophy, white matter signal abnormalities, progressive cortico-subcortical atrophy, particularly within the cerebellar vermis, enlarged or partially empty sella turcica and prominent Virchow–Robin spaces.30,40,41

Figure 10. Dysostosis multiplex in a young child with mucoli- pidosis II (I-cell disease). Anteroposterior radiograph of the forearm demonstrates curvature of the distal radius leading to Glycogen storage diseases tilting of the radial metaphysis towards the ulna (arrow) and The glycogen storage disorders (GSDs) result from a genetic thickening of the diaphyseal regions (arrowheads). defect in enzymes regulating synthesis or degradation of glyco- gen. In contrast to the other GSDs, the underlying pathogenesis

Figure 12. Dysostosis multiplex in a young child with mucoli- pidosis III alpha/beta (pseudo-Hurler polydystrophy). Radio- graph of the hand demonstrates bullet-shaped phalanges (arrowhead) and widened metacarpals pointed proximally (arrows).

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Figure 13. Dysostosis multiplex in an older child with alpha- mannosidosis. Single frontal radiograph of the chest and abdomen demonstrates mild broadening of the ribs bilaterally

(arrows). mental Develop- Normal intelligence Normal intelligence orders) Neurological/ ophthalmological Widening of the lateral ventricles, delayed myelination, abnormal periventricular white matter signal on MRI Photophobia (due to corneal cystine crystals) Musculoskeletal Hypotonia, fatty atrophy of muscles Rickets: metaphyseal cupping, osteopenia, fractures renal Clinical and radiological characteristics Gastrointestinal/ Hepatomegaly Fanconi syndrome, medullary nephrocalcinosis respiratory Cardiovascular/ Respiratory distress due to hypotonia (infant and adult onsets), cardiomegaly/ cardiomyopathy (earlier age onset) in glycogen storage disease Type II (GSD II) is due to a defect in lysosomal metabolism.42 Genetic, clinical and radiological fea- tures of GSD II are summarized in Table 3. substance Accumulated Glycogen Cystine None Glycogen storage disease II: Pompe disease GSD II or Pompe disease is caused by a deficiency in the lyso- somal a-glucosidase enzyme, with glycogen abnormally accu- ; GSD, glycogen storage disorder; MPS, mucopolysaccharidosis. mulating within the lysosomes of several cell types, particularly 43,45 Deficiency Alpha- glucosidase muscle cells. This disease is inherited in an autosomal re- Cystinosin (cystine transporter) cessive pattern.43 The combined incidence of all forms of GSD II varies from 1.00/100 000 in people of European descent to 7.14/ 31 43

100 000 in African-Americans. Acid a-glucosidase , q25.3 – 17p13 Gene GAA mutation and locus

GSD II is subdivided into infantile-onset and late-onset disease, ; (inheritance) GAA 17q25.2 (AR) with infantile-onset disease further categorized into classic and CTNS (AR) non-classic types.43,45 Clinical features of the infantile-onset type include myopathy with hypotonia, respiratory distress, car- Cystinosin 44 , diomegaly and hypertrophic cardiomyopathy, hepatomegaly, , 43 feeding difficulties, macroglossia and failure to thrive. In- CTNS telligence is usually normal.43,46 Hepatomegaly and respiratory 1.0 births – 100 000 live infections are clinical features seen with infantile-onset GSD Incidence per 1.00 (European descent) to 7.14 (African-American descent) 0.5 which are also seen with MPS I.43 However, dysostosis multiplex is not a feature of GSD II in contrast to MPS I and several of the other LSDs previously discussed.47

The classic infantile-onset type often presents by the first Disease Glycogen storage disease II: Pompe 43 Amino acid disorder: cystinosis month of life and is usually fatal by the first year if untreated. Table 3. Summary of clinical and radiological manifestations of Pompe disease and cystinosis (glycogen storage disorders and amino acid storage dis AR, autosomal recessive;

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Figure 14. Central nervous system changes in a child with Figure 16. Hypophosphataemic rickets in a child diagnosed glycogen storage disorder II (Pompe disease). Axial MRI fluid- with cystinosis. Anteroposterior radiograph of the knees demon- attenuated inversion–recovery image of the brain demonstrates strates metaphyseal cupping and fraying (arrows) consistent with abnormal hyperintense signal in the periventricular white matter rickets. (arrows). Signal is non-specific, but may indicate incomplete myelination, dysmyelination or demyelination.

of the lateral ventricles, delayed myelination and abnormal peri- – ventricular white matter signal on MRI (Figure 14).48 50

Late-onset GSD II can present at various ages and may be further subdivided into juvenile late-onset and adult late-onset forms.45 Hypotonia and cardiomegaly are seen earlier in the first year of The juvenile late-onset type occurs between 2 and 18 years old, life in the classic type of GSD II than in the non-classic infantile and the adult late-onset type occurs after 18 years old.45 type.46 Death usually occurs during the first year caused by cardiorespiratory failure in the classic type, with patients often having more severe cardiomegaly than the non-classic type, Figure 17. Fractures in a child diagnosed with cystinosis. including left ventricular outflow obstruction from hypertro- Coronal short tau inversion–recovery MR image of the pelvis phy.43,46 In the non-classic type, death usually occurs after the demonstrates insufficiency fractures bilaterally along the first year from respiratory insufficiency.46 Hypotonia contributes proximal femur (arrows). to respiratory insufficiency in both infantile types, and recurrent respiratory infections or pneumonia are commonly seen.45 Patients with infantile-type GSD II have been reported to have abnormal accumulation of glycogen within the CNS.48 Neuro- imaging findings in patients with infantile GSD II include widening

Figure 15. Diffuse fatty atrophy of the proximal lower limb muscles in an adult with late-onset-type glycogen storage disorder II (Pompe disease) seen on this axial T1 weighted MR image of the thighs.

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Cardiomegaly, macroglossia and hepatomegaly are rarer in may also exhibit renal and ocular problems, but these are less patients with late-onset type of GSD II, particularly the older severe and occur later in onset than in the infantile nephropathic the age of onset.43,45 Skeletal myopathy and respiratory in- type.52,53 The ocular or non-nephropathic type is seen in adults, sufficiency are characteristic features of late-onset type GSD who manifest ocular problems rather than renal disease.52,53 II, and there is usually greater progression of these features with earlier age of onset.43 Proximal muscle weakness may In summary, cystinosis predominantly includes renal, ocular and be the presenting feature in late-onset-type GSD II patients, osseous manifestations depending on the age of onset. In con- and musculoskeletal imaging may demonstrate fatty atrophy trast to the majority of previously discussed LSDs, osseous in- ofthepelvicgirdle,paraspinal,psoasandthighmuscles volvement is seen as rickets rather than dysostosis multiplex. (Figure 15).51 Respiratory failure is a common cause of death in these patients.43,45 CONCLUSION The LSDs encompass a very large group of rare disorders.1 Amino acid disorders Attempting to master their multiple clinical and radiological Cystinosis manifestations may seem overwhelming. However, each disease LSDs may also result from abnormal accumulation of amino has an inherent fundamental problem of a metabolic pathway acids in the lysosome. Cystinosis is an LSD because of a de- disturbance with abnormal storage of material resulting in cell, ficiency in cystinosin, a cystine transporter within the lyso- tissue or organ dysfunction.1 Knowing which organ systems are somal wall, resulting in abnormal accumulation of cystine crystals predominately affected and how they are affected within each within the lysosome.52,53 Cystinosis has an autosomal recessive disease is invaluable in understanding the disease manifestations. inheritance pattern, and an incidence of 0.5/100 000–1.0/100 000 Key features of many of the non-lipid or extralipid LSDs are live births.44 Genetic, clinical and radiological features of cysti- discussed in the article, with several of the diseases having nosis are summarized in Table 3. There are three variants of similarities to MPS I or Hurler syndrome. Clinicians and radi- cystinosis, which include nephropathic, intermediate nephro- ologists having knowledge of the basic clinical and radiological pathic and ocular or non-nephropathic types.44,53 features of MPS I can be helpful in recognizing and diagnosing patients with LSDs. However, the key clinical similarities and Nephropathic type (infantile) is the most common and severe differences between each disease discussed in this article, and form, with onset in infancy.52,53 Patients with the infantile MPS I may help to further identify the storage disorder and nephropathic type may have renal tubular Fanconi syndrome, diagnose the patient with the correct LSD. Early recognition with hypophosphataemic rickets, impaired growth, hypothyroidism the correct diagnosis is a priority considering the availability of and corneal cystine crystals resulting in photophobia.44,53 In- new treatment options for several diseases in the setting of po- telligence in cystinosis is usually normal.44,53 Imaging findings tentially devastating consequences if left untreated. include changes associated with rickets, including metaphyseal cupping and fraying, osteopenia and fractures (Figures 16 and ACKNOWLEDGMENTS 17). Additionally, renal imaging may demonstrate findings of The location of the study, facilities and the study subjects were medullary nephrocalcinosis.53 The juvenile or intermediate type recruited at Emory University Affiliated Hospitals, Atlanta, GA.

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