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urrent Strategies in theanagement of Lysosomal Storage Diseases

ryce A. Heese, MA, MD

Lysosomal storage diseases (LSDs) comprise a diverse group of over 40 clinically distinctinherited disorders. LSDs are progressive and may present at any age affecting any numberof tissues and organ systems. They result from a genetic defect in cellular transport ormetabolism of molecules within the lysosome. Treatment is directed toward symptomaticcare of secondary complications for most of these diseases. For some individuals, hema-topoietic stem cell transplantation or enzyme-replacement therapy can be effective. How-ever, limitations in these therapies still exist. To date, there is no cure for any of the LSDs.Early diagnosis and treatment is essential for optimal treatment; this lends support toimplementing mass newborn screening for LSDs.Semin Pediatr Neurol 15:119–126 © 2008 Elsevier Inc. All rights reserved.

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he lysosome is an intracellular organelle essential for thebiochemical breakdown of several molecules, such as

lycosaminoglycans (GAGs), oligosaccharides, sphingolip-ds, and other lipids. Defects of lysosomal metabolism, orysosomal storage diseases (LSDs), comprise a diverse groupf over 40 inherited disorders. These disorders are caused byutations in genes that code for lysosomal enzymes, trans-ort proteins, or other gene products essential for a func-ional lysosomal system. As a result, abnormal accumulationor storage) of substrates within the lysosome leads to pro-ressive cellular impairment and dysfunction of numerousrgans and systems.The genes that code for lysosomal proteins are present in

very cell. However, because of unique metabolic require-ents of different cell types, a defect in a lysosomal enzymeay have a significantly greater impact in a certain tissue

ompared with other tissues. For example, the enzyme-acetyl-galactosamine-6-sulfate is critical in the lysosomalreakdown of keratin sulfate, primarily found in the skeletalystem. A defect in this enzyme, as in mucopolysaccharidosisMPS) type IVA (Morquio syndrome), causes abnormal stor-ge of keratin sulfate in the skeletal system, thus resulting inevere skeletal growth problems, dysostosis multiplex, andoint disease. Cardiac valve disease and corneal clouding arelso features of Morquio syndrome, but, in general, this en-

rom the Department of Pediatrics, Division of Genetics and Metabolism,University of Florida, Gainesville, FL.

r Heese is supported in part by an educational grant from Genzyme Cor-poration.

ddress reprint requests to Bryce A. Heese, MA, MD, Department of Pediatrics,

sPO Box 100296, Gainesville, FL 32610. E-mail: heeseba@peds.ufl.edu

071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.spen.2008.05.005

yme defect relatively spares most nonskeletal organ systems.lternatively, the lysosomal enzyme, galactocerebrosidase, isssential for metabolizing galactosylceramide, a sphingolipidound in myelin. Individuals with a defect in this enzymeKrabbe disease [globoid cell leukodystrophy]) will presentith progressive neuroregression. Other defects of sphingo-yelin degradation, such as metachromatic leukodystrophy

r GM2 gangliosidosis, also have predominantly abnormalentral nervous system (CNS) findings.

LSDs typically are not evident at birth, and they are com-only progressive in nature. Diagnosis can be difficult be-

ause of the marked variability in clinical presentation amonghe group and the subtle progressive nature of many of theseisorders. An astute pediatrician may be able to quickly iden-ify problems in an infant with classic MPS IH (Hurler syn-rome) with coarsening features and neurodegenerative de-line. However, more attenuated forms of MPS I (Scheieyndrome), with slowly progressive mild coarsening of fea-ures and normal cognition, may go unnoticed for years withnly vague nonspecific symptoms being reported.Among specific enzyme defects, marked variability in phe-

otypic presentation also exists. For example, Pompe diseaseacid maltase deficiency) is a disorder of glycogen metabo-ism that manifests as severe infantile onset with hypotonia,ypertrophic cardiomyopathy, and failure to thrive. Theame enzyme defect can also result in adult-onset proximaluscle weakness, respiratory insufficiency, and complete

ack of cardiac findings. Of note, Pompe disease is also re-erred to as glycogen storage disease (GSD) type II. However,nlike other GSDs, Pompe disease is functionally a lysosomal

torage disease and thus is the only GSD considered in this

119

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eview. Niemann Pick disease type C typically presents withignificant hepatosplenomegaly, ataxia, and dystonia in earlyhildhood. However, a late-onset variant of Niemann Pickisease can present in adolescence or even adulthood withrogressive behavioral and psychiatric problems without vis-eral manifestations. Cystinosis is a unique LSD caused by aefect in a lysosomal (anion) transporter that results in theccumulation of cystine crystals, particularly in renal tissuesnd in the cornea. This disorder generally presents in earlyhildhood with significant growth failure, rickets, renal Fan-oni syndrome, and photophobia. Individuals are often re-erred to and/or diagnosed by pediatric nephrologists andypically progress to renal failure. However, an adult variantf this disorder can present with only photophobia caused byhe accumulation of crystals within the cornea.

The ability to describe each LSD in detail is beyond thecope of this review. Table 1 lists over 40 known lysosomalefects and their classic phenotype, with the understandinghat most of these diseases can have quite variable presenta-ions. Diagnostic testing and treatments specific to each dis-ase are also listed in Table 1.

Classically, the treatment of LSDs has been limited toymptomatic care of disease manifestations. Recent decadesave observed the development and continual improvementf therapies such as hematopoietic stem cell transplantationHCT) and enzyme-replacement therapy (ERT) for selectSDs. For many, this has led to significant clinical improve-ent and enhanced quality of life. It has been shown that

arlier diagnosis and treatment improves overall outcome.1

herapy should, ideally, be initiated presymptomatically torovide the best outcome. This may be possible for ansymptomatic patient diagnosed because of a known familyistory; however, most patients who are diagnosed clinicallyill be symptomatic by the time therapy is initiated, regard-

ess of how astute the clinician may be. This underscores theenefits to developing and introducing mass newborncreening for LSDs.

CTCT is an important treatment in several inherited metaboliciseases including LSDs. The objective of HCT is to engraftealthy cells (without genetic defect) into a patient withoutunctional enzyme.

The first HCT for an LSD was in an individual with Hurleryndrome in 1980.2 The relative success of this procedureas been followed by over 900 HCTs for inherited metaboliciseases with mixed results.3 Most clinical information onCT in LSDs comes from patients with Hurler syndrome andrabbe syndrome, but there is limited experience in manyther conditions within this group.4-8 For disease types withignificant CNS deterioration, such as MPS type I (Hurler) orrabbe disease, HCT is known to only be effective in theeonatal or presymptomatic stage of the disease. Another

imitation of HCT is that skeletal disease is not affected byreatment. The greatest challenge to HCT is transplant-re-ated mortality rate, which has been reported between 10%

nd 25%.9 Continually improving techniques and the use of s

lternative stem cell sources, such as umbilical cord bloodtem cells, will likely lead to better outcomes in the future.10

ll things considered, HCT remains a viable option for somendividuals with LSDs.

Based on clinical experience with transplant in LSDs, Pe-ers and Steward1 suggest that HCT be considered in theollowing diseases: MPS type IH (Hurler syndrome), MPSype VI (Marateaux-Lamy syndrome), MPS type VII (Sly syn-rome), Krabbe disease, metachromatic leukodystrophy, al-ha-fucosidosis, alpha-mannosidosis, Gaucher disease (al-hough ERT is available and is the first-line treatment for type), and Niemann-Pick disease type B. For most other lysoso-al defects, there are either limited or discouraging data to

ecommend HCT. Because of the progressive nature and vari-bility of each disease, a comprehensive, multidisciplinarypproach should be used in each case to determine whetherpatient is a good candidate for HCT.1 Ideally, this should beerformed in a center with experience in LSDs.

RThe concept of enzyme replacement was realized decades agoith observations in experimental fibroblast cell lines of MPS

ype I and MPS type II patients in whom the respective en-yme defect in either cell type was corrected by culturingoth cells together.11 Lysosomal enzymes and proteins pro-uced in the cell are posttranslationally modified with certainarkers, such as a mannose-6-phosphate moiety. These pro-

eins are directed to the lysosome in which specific mem-rane receptors (in this instance, a mannose-6-phosphateembrane receptor) help endocytose the protein for use in

he lysosome. Lysosomal proteins may also be excreted out ofhe cell and taken up by other cells and specific lysosomalembrane receptors within that cell, as was observed by the

arly studies of mixing MPS I and MPSII cell lines.12 Thisoncept is the basis for current ERT for 6 of the LSDs (Fig 1).

Enzyme replacement first became clinically available withood and Drug Administration approval in 1991.13 Imiglu-erase is a recombinant enzyme for the treatment of individ-als with nonneuronopathic (type 1) Gaucher disease. It haseen reported to reduce hepatosplenomegaly, improve ane-ia and thrombocytopenia, and reduce episodes of pain cri-

es in these patients.13,14 Because the recombinant enzymeoes not cross the blood-brain barrier, it is not effective inype 2 Gaucher disease patients with severe CNS abnormal-ties.15

Fabry disease is an X-linked disorder that typically pre-ents in adolescent or adult males with acroparesthesia, hy-ohidrosis, and vague gastrointestinal symptoms and often

eads to progressive renal failure and cardiomyopathy. Un-reated, the life expectancy for males with Fabry is reported toe 40 to 55 years. Although this is an X-linked disorder,emales are indeed symptomatic.16 ERT using recombinantlpha-galactosidase A has been clinically available for pa-ients with Fabry disease since 2003. Improvement in painnd gastrointestinal symptoms has been reported, but long-erm studies are required for evaluating its efficacy with re-

pect to life-threatening complications.17,18

Table 1 LSDs, Typical Presentation, Unique Diagnostic Features, and Disease-Specific Treatments and Investigational Therapies

Disorder (enzyme or defect) Clinical Manifestations Diagnostic Features Specific Treatment

Defects in Glycosaminoglycan DegradationMPS type I; Hurler & Scheie s. (alpha-L-

iduronidase)Coarse, hydrocephalus, dysostosis multiplex,

valve, airway obst; cornea; MR in Hurler,milder in Scheie s.

Urine GAG screen; enzyme (leuk, fibr);molecular

ERT; HCT for Hurler Investigational:intrathecal ERT

MPS type II; Hunter syndrome(iduronate-2-sulfatase)

X-linked; MR, coarse, hydrocephalus,dysostosis multiplex, airway obstruction,valve

Urine GAG screen; enzyme (leuk, fibr);molecular

ERT; investigational: intrathecalERT

MPS type III; Sanfilippo syndrome (typesA-D; different enzymes)

MR, behavior and aggression probs., seizures Urine GAG screen; enzyme (leuk, fibr);molecular

MPS type IV; Morquio syndrome (typesA & B; different enzymes)

Normal cognition, coarse, dysostosismultiplex

Urine GAG scrn; Enzyme (leuk, fibr);Molecular

MPS type VI; Maroteaux-Lamy s.(arylsulfatase B)

Normal cognition, coarse, dysostosismultiplex, HSM, valve

Urine GAG scrn; Enzyme (leuk, fibr);Molecular

ERT; HCT for severe form

MPS type VII; Sly syndrome (beta-glucuronidase)

MR, coarse, dysostosis multiplex, HSM,Hydrops fetalis

Urine GAG screen; enzyme (leuk, fibr);molecular

MPS type IX; Natowicz syndrome(hyaluronidase)

Skeletal problems, periarticular soft-tissuemasses (single patient)

Molecular

Defects in Glycoprotein (oligosaccharide; carbohydrate side-chain) Degradationalpha-Mannosidosis (alpha-

mannosidase)MR, coarse, cerebellar ataxia, psychiatric,

dysostoses multiplex, corneal, HSMVacuo lymph; urine oligo screen; enzyme

(leuk fibr); molecularHCT

beta-Mannosidosis (beta-mannosidase) MR, coarse, hypotonia, spasticity, neuropathy Urine oligo screen; enzyme (leuk fibr);molecular

Fucosidosis (alpha-fucosidase) MR, coarse, spasticity, cardiomegaly,myoclonic

Urine oligo screen; enzyme (leuk fibr);molecular

HCT (limited experience)

Sialidosis; Mucolipidosis type I (alpha-N-acetyl neuraminidase)

(type I) Vision, myoclonic, spasticity,neuropathy; (type II) coarse, dysostosismultiplex, cherry red

Urine oligo screen; enzyme (fibr);molecular

Aspartylglucosaminuria(aspartylglucosaminidase)

MR, coarse, behavioral, HSM Vacuo lymph; urine oligo screen; enzyme(leuk fibr); molecular

HCT (limited experience)

Schindler disease (alpha-N-acetyl-galactosaminidase)

MR, spasticity, myoclonic; adult onset(Kanzaki d.) milder, angiokeratoma corporisdiffusum

Vacuo lymph; urine oligo screen; enzymestudies (leuk fibr); molecular testing

Defects of Glycolipid Degradation (particularly, sphingolipids found in nervous tissue)Globoid cell leukodystrophy or Krabbe

disease (galactocerebrosidase)MR, leukodystrophy, spasticity, neuropathy,

(late-onset variants too)Enzyme (leuk fibr); molecular HCT Investigational: ERT, small

molecule therapyMetachromatic leukodystrophy

(arylsulfatase A)MR, leukodystrophy, spasticity, neuropathy,

(late onset variants too)Urine sulfatides, Ultrastructure lipid

deposits (bx); enzyme (leuk, fibr);molecular

HCT Investigational: ERT

GM1-gangliosidosis (beta-galactosidase) MR, coarse, hypotonia, cherry red, dysostosismultiplex, HSM, hydrops fetalis, (latevariants too)

Urine oligo screen; enzyme (leuk fibr);molecular

HCT (limited experience)

Lyosomalstorage

diseases121

Table 1 Continued

Disorder (enzyme or defect) Clinical Manifestations Diagnostic Features Specific Treatment

GM2-gangliosidosis; Tay-Sachs (alpha-hexosaminidase A; beta-subunit)

MR, spasticity, myoclonic, cherry red, (lateronset variants too)

Urine oligo screen; enzyme (leuk fibr);molecular

Investigational: small-moleculetherapy

GM2-gangliosidosis; Sandhoff d. (beta-hexosaminidase A & B; alpha subunit)

MR, spasticity, myoclonic, cherry red Urine oligo screen; enzyme (leuk, fibr);molecular

Gaucher disease types I, II, III (beta-glucocerebrosidase)

(Type I) later onset, HSM, anemia,thrombocytopenia, bone pain (Type II)MR, spasticity, myoclonic, HSM, hydropsfetalis

Ultrastructure lipid storage in macrophages(bone marrow); enzyme (leuk, fibr);molecular

ERT; HCT type I; Small moleculetherapy

Fabry disease (alpha-galactosidase A) X-linked; pain crises, acroparesthesia,hypohidrosis, angiokeratoma, corneal,kidney, cardiovascular; females affected

Enzyme (leuk, fibr); molecular ERT

Farber disease (ceramidase) MR, neuropathy, hoarse, skin nodules Cellular ultrastructure (nodule bx); enzyme(fibr); molecular

HCT (limited experience)

Niemann-Pick type A & B (sphingomyelinase) Type A (neuropathic): MR, myoclonic,cherry red, cornea, lung disease, HSMType B: HSM, lung disease

Vacuo lymph; Ultrastructure (bone marrowbx); enzyme (leuk, fibr); molecular

For type B: HCT (limitedexperience); Investigational:ERT

Defect in Glycogen DegradationPompe disease; GSD type II (alpha-

glucosidase)Infantile: hypotonia, myopathy, hypertrophic

cardiomyopathy, FTT, Adult: proximalmuscle weak, no cardiac

Creatine kinase; vacuo lymph; Urine oligoscreen; enzyme (fibr); molecular

ERT

Defect in Polypeptide DegradationPycnodysostosis (cathepsin K; cysteine

protease)Skeletal deformation, fractures Radiologic; molecular

Cholesterol and Lipid Transport DefectsCeroid lipofuscinosis CLN1 (palmitoyl

protein thioesterase 1) CLN2 (tripeptidylpeptidase 1) CLN3 (membrane protein)

Psychomotor regression, myoclonic,blindness CLN1, CLN2, CLN3 and others

Vacuo lymph; Ultrastructure deposits (skin,nerve bx, leuk); enzyme (leuk fibr forCLN1); molecular

HCT for CLN1 & CLN2 (limitedexperience)

Niemann-Pick d. type C (intracellularcholesterol esterification & transport)

Psychomotor regression, hypotonia, liverdisease, vertical supranuclear palsy,dystonia, seizures; later onset variantswith psychiatric and dementia

vacuo lymph; ultrastructure (bone marrowbx); in vitro cholesterol esterification(fibr); molecular

Investigational: small moleculetherapy

Wolman disease (acid lipase; cleavecholesterol esters from LDL)

Psychomotor regression, FTT, diarrhea,stearrhea, HSM, adrenal calcifications;adult variants with atherosclerosis

Serum cholesterol; vacuo lymph; enzyme(leuk)

Defects in Multiple Lysosomal EnzymesMultiple sulfatase deficiency (sulfatase-

modifying factor 1)Features of MLD, and MPS types II, III, IV,

& VI, as well as ichthyosis and proptosisUrine GAG screen, enzyme (numerous

sulfatase deficiencies); molecularGalactosialidosis (protective

protein/cathepsin A)(early severe) MR, coarse, spasticity,

cherry red, cornea, dysostosis multiplex,HSM, hydrops fetalis, (late onset var.)

Vacuo lymph; Urine oligo screen; Enzyme(fibr); increased serum lysosomalenzymes; molecular

122Bryce

A.Heese

Table 1 Continued

Disorder (enzyme or defect) Clinical Manifestations Diagnostic Features Specific Treatment

Mucolipidosis type II (I-Cell d.) & typeIII (pseudo Hurler disease) (N-acetylglucosamine 1-phospotransferase)

Similar to MPS I: MR, hydrocephalus, coarse,dysostosis multiplex, valve, HSM Type III ismilder disease

Vacuo lymph; urine oligo screen;enzyme (fibr);increased several serumlysosomal enzymes; molecular

Lysosomal transport defectsCystinosis (cystosin; lysosomal

membrane transporter)Renal tubular fanconi, FTT, rickets, corneal

crystals Non-nephrotic/adult–photophobiaonly

Corneal crystals (slit lamp);Ultrastructure crystals (bone marrow,conjunctiva, renal); leukocyte cystine;molecular

Oral cysteamine, renal transplant;investigation: cysteamine eyedrops

Cobalamin F Defect (lysosome releaseof Vit B12)

MR, FTT, seizures, rash, stomatitis, Serum/urine methylmalonic acid, Plasmahomocysteine

Vitamin B12

Mucolipidosis IV (mucolipidin;receptor-stimulated cation channel)

MR, spasticity, cornea, retinopathy Plasma gastrin; vacuo lymph;ultrastructure inclusions (skin, cornealbx); molecular

Sialic acid storage disease (sialin;lysosomal anion transporter)

MR, coarse, hypotonia, cerebellar ataxia HSMAdult (Salla d.) slow progressive onset

Sialic acid in urine; molecular

Sialuria (UDP-N-acetylglucoamine-2-epimerase)

MR, coarse, hypotonia, myoclonic, HSM Sialic acid in urine; molecular

Chediak-Higashi syndrome (lysosomaltrafficking regulator)

Psychomotor regression, oculocutaneousalbinism, bleeding diathesis, recurrentinfection

Ultrastructure granules (leuk, bonemarrow)

HCT

Danon disease (lysosome-associatedmembrane protein-2)

X-linked, MR, cardiomyopathy, muscle weak,retinopathy

Creatine kinase; vacuoles (muscle);molecular

Heart transplant

Unknown mechanism (speculated lysosomal storage disease)Marinesco-Sjögren syndrome (ER

glycoprotein enhances proteinsynthesis)

MR, microcephaly, FTT, cerebellar ataxia,weakness, spasticity, cataracts, skeletal,hypogonadotropic hypogonadism

Ultrastructure inclusion bodies (leuk);molecular

Hermansky-Pudlak syndrome (severalgenes implicated)

Oculocutaneous albinism, bleeding diathesis,pulmonary fibrosis, granulomatous colitis

Ultrastructure absent dense bodies inplatelets; Molecular

Geleophysic dysplasia (not known) MR, seizures, happy-nature appearance,skeletal, cardiac valve, hepatomegaly

Ultrastructure storage vacuoles (live,cartilage, heart)

Defects of Activator ProteinsGM2-gangliosidosis AB-variant (beta-

hexosaminidase activator)Features of GM2 gangliosidosis: MR,

hypotonia, cherry redEnzyme (leuk, fibr); molecular

Saposin A; Krabbe variant Features of Krabbe (single case report) Enzyme; molecularSaposin B; MLD variant Features of MLD Enzyme; molecularSaposin C; atypical Gaucher Features of Gaucher types II/III Ultrastructure (nerve); molecular

Many lysosomal storage diseases have a wide clinical spectrum; however, only common features are noted here.Abbreviations: MR � mental retardation, includes developmental delay and developmental regression; myoclonic � myoclonic seizures; HSM � hepatosplenomegaly; valve � cardiac valve disease;

FTT � failure to thrive; cornea � corneal clouding or crystals; cherry red � cherry red macular spot; GAG � glycosaminoglycans; oligo � oligosaccharides; vacuo lymph � vacuolatedlymphocytes; leuk � leukocytes; fibr � fibroblasts; bx � biopsy; ER � endoplasmic reticulum; GSD � glycogen storage disease; MLD � metachromatic leukodystrophy.

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124 Bryce A. Heese

Laronidase was approved in 2003 for use in MPS I witheported improvements in hepatosplenomegaly and respira-ory disease and showing a decrease in urinary glycosamino-lycan excretion.19 However, HCT remains the mainstay ofherapy for MPS I but at the risk of HCT-related complica-ions.

Recombinant arylsulfatase B was approved for clinical usen MPS VI (Maroteaux-Lamy syndrome) in 2005 and haseen associated with improvements in hepatosplenomegaly,

oint movement, cardiopulmonary function, and pain as wells reduced excretion of urinary glycosaminoglycans.20

Alglucosidase alpha is Food and Drug Administration ap-roved for use in infantile Pompe disease. A portion of infantsho are diagnosed and treated with ERT before 6 months of

ge had improved survival and quality of life compared withhe observed natural history of the disease, yet, for unknowneasons, a subset of the treated cohort did not show effectsrom ERT.21 ERT studies for late-onset Pompe disease arengoing.The latest recombinant human enzyme available clinically

s idursulfase for the treatment of MPS II (Hunter syndrome)atients. Clinical trials showed improvement in cardiopul-onary disease and hepatosplenomegaly and decreased ex-

retion of urinary glycosaminoglycans.22

There are a number of challenges to ERT. ERT has beenhown to halt progression and even reduce the disease bur-

Figure 1 A depiction of ERT. A cell with a dysfunctiowith abnormal accumulated storage material (bottom lmodified with a mannose 6-phoshate group, is (1) targeendosome combines with a dysfunctional lysosome, andfunctional exogenous enzymes. The accumulated storagand structure of the lysosome. (Color version of figure i

en in certain tissues. However, it is apparent that ERT has v

ittle effect on the brain, skeletal tissue, and valvular heartisease in LSDs. Infusion-related events have been noted in

ntravenous ERT. Mild allergic reactions, such as urticaria,ever, and chills, are typically treatable with antihistaminesnd nonsteroidal antiinflammatory drugs and reduction innfusion rate. The development of neutralizing antibody toecombinant enzyme followed by clinical decline has beeneported; however, most patients who seroconvert developolerance to the enzyme. Rarely, a patient will have to discon-inue therapy because of adverse infusion reactions.23,24 Life-ong, frequent infusions are another challenge of ERT that

ust be weighed against the burden of disease. Current treat-ent protocols consist of frequent intravenous access and

nfusion, which vary from weekly to monthly depending onhe protocol.25 In some instances, this may require long-istant travel to an infusion facility. However, local and even

n-home infusions are available and can alleviate some of theurden of infusion therapy.Alternative delivery of recombinant enzymes, such as in-

rathecal injection of recombinant enzymes in Hurler syn-rome, has been proposed and is currently investigational.26

The estimated cost of ERT is between $90,000 to $565,000US), depending on the disease (therapy) and patientize.25,27 Costs are driven by extraordinary financial invest-ent in research and development taken on by pharmaceu-

ical companies who take a risk in developing therapies for

somal enzyme is shown exhibiting swollen lysosomesxogenous enzyme (or recombinant enzyme), which iscellular membrane receptors and endocytosed. (2) Thedefective enzymes within the lysosome are replaced by

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osts and Food and Drug Administration approval fees areessened by the Orphan Drug Act of 1983, without whichhere may not have been incentive to develop ERT for clinicalse. However, it has also been argued that this act, whichrants 7 years exclusivity, also eliminates competition in set-ing costs.27 To the credit of the respective ERT pharmaceu-ical companies, each has set up some form of patient-sup-ort system to help gain coverage and access and to take thenancial stress off of the clinical staff and patients.

mall-Molecule Therapyor many LSDs, there is a promise of continual technical

mprovements in existing therapies. However, even success-ul HCT and ERT will likely continue to have limitations,articularly in the treatment of CNS and skeletal manifesta-ions that occur in most of these disorders. A significant fieldf research deals with small-molecule therapies that could beelevant to LSDs. The hope of this treatment is to offer simplelikely oral) medication that can cross the blood-brain barriernd be more readily distributed throughout the body. Theseompounds are directed at either enhancing the existing en-yme function, as in chaperone molecules, or by limiting theroduction-offending substrate (or abnormal storage mate-ial), as in substrate-reduction therapy.

Chaperones are small molecules whose role is to enhancehe formation of protein products of a cell. Because a proteins transcribed from RNA, it must be correctly folded into aunctional product. Misfolded proteins are likely nonfunc-ional and more rapidly degraded by cellular proteases.haperone therapy may be beneficial in inherited diseases

hat are caused by genetic mutations causing small confor-ational changes in the protein, often missense mutation or

rame-shift deletions.28 In this treatment modality, a chaper-ne would assist a protein in folding and help avoid degra-ation to produce a (at least partially) functional enzyme.iseases caused by null mutations, resulting in no gene prod-ct, would not be expected to be aided by chaperone therapyo this type of therapy would be mutation dependent.

Substrate-reduction therapy is directed at reducing the ac-umulation of storage molecules by inhibiting their initialormation. N-Butyldeoxynojirmimycin is the only drugithin this category that is Food and Drug Administration

pproved for use in an LSD, specifically Gaucher disease.29

his compound works by inhibiting the enzyme ceramidelucosyltransferase from producing glucosylceramide, whichs accumulated in this disease. The recommended use of N-utyldeoxynojirmimycin would include the treatment ofdults with mild or moderate Gaucher disease who cannot oro not wish to be on ERT or Gaucher patients with persistentisease despite ERT.30 Trials are also ongoing for the efficacyf N- butyldeoxynojirimycin in patients with Niemann-Pickype C because this condition is also associated with accumu-ation of glucosylceramide.31 Another trial using isoflavone as

substrate inhibitor in MPS type III is being evaluated.32 s

ene Therapyene therapy is the insertion of a functional gene to produceworking enzyme and replace the defective one and prom-

ses a potential cure for many inherited diseases includingSDs. Currently, several different LSD animal models areeing studied by either direct gene transfer using viral vectorsr by genetically altering defective hematopoietic stem cellsnd then returning them to the donor.24 A small (n � 3)uman clinical trial in Gaucher disease did not show signif-

cant clinical improvement.33 Since that time, clinical trialsor gene therapy have been limited because of safety concernsesulting from a few case reports of complications in otheriseases.34,35

ewborn Screenings treatment options for LSDs improve, there is a clear ad-antage for early, preferably presymptomatic, diagnosis. Thisends support to developing newborn screening for thisroup of disorders. Since its inception in the early 1960s,ndividuals with inborn errors of metabolism, particularlyhenylketonuria, and other inherited diseases have benefitedrom early, presymptomatic treatment.36

For decades, most states screened for only a handful ofisorders as a result of the complexity of screening for indi-idual disorders. One of the most significant advances in theast decade has been the implementation of a high-through-ut, multiplex technique using tandem mass spectrometry tocreen for dozens of organic acidemias, amino acidopathies,nd fatty acid oxidation defects. Today, almost every state inhe United States and numerous countries have adopted thiscreening modality.37 This has also paved a way for poten-ially adding a multiplex screening technique aimed at de-ecting LSDs. Methods have been developed and are cur-ently being piloted using either tandem mass spectrometrydentification of enzyme reaction products or immunologicrotein assay of several markers. Both methods have beenalidated to detect several different LSDs, and both are re-orted to be capable of being high throughput for masscreening at costs comparable to current screening meth-ds.38-40 It is difficult to determine when/if LSD screening wille adopted by most screening programs; however, it is note-orthy that the state of New York has been screening forrabbe disease since 2006.41

ummarySDs comprise a diverse group of disorders; each is relativelyare, but, as a group, they have an estimated incidence ofbout 1 in 7,000. For most LSDs, management is still re-tricted to treating secondary complications of the disease.owever, within the past decade, treatment options, partic-larly HCT and ERT, have substantially changed manage-ent in a few lysosomal diseases. These therapies are di-

ected at the primary (enzymatic) defect and have been

hown to halt progression and even reverse some features of

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126 Bryce A. Heese

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