Lysosomal Disorders - Peds

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Select Disorders of ComplexMolecule Biosynthesis

PART 9


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IN THIS PART

Chapter 43 Lysosomal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721

Chapter 44 Purine and Pyrimidine Metabolism . . . . . . . . . . . . . . . . . . . . . . .757

Previous page: Computer generated image of the plasma membrane of a cell showing sugars (red) protrudingfrom the outer surface. The sugars are linked to membrane proteins and lipids forming glycoprotein and glycolipidgroups. These surface sugars act as receptors and are responsible for recognizing and binding molecules likehormones or toxins. The plasma membrane itself is formed of a lipid bilayer (green) with integral transmembraneproteins (purple). Inside the cell is a stack of Golgi apparatus (lower right) producing lysosomes (blue spheres).


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C H A P T E R

INTRODUCTION

Lysosomes are spherical organelles, con-tained by a single-layer membrane, that arepresent in all nucleated cells (1). Lysosomesoriginate in the Golgi apparatus, with thedigestive enzymes manufactured in the the

rough endoplasmic reticulum. An integralpart of the intracellular recycling process,lysosomes contain hydrolytic enzymes thatdigest obsolete cell components and de-grade complex cellular substrates such asglycoproteins, mucopolysaccharides (gly-cosaminoglycans), oligosaccharides, andlipids into simpler components in a step-wise manner. A block in the degradation ofthese substrates leads to abnormal accumu-lation of complex macromolecules withinlysosomes. Lysosomal disorders (LDs) are inheritedconditions that are caused by defects in en-zymes, enzyme activator proteins, mem-brane proteins, transporters, or enzyme tar-geting to the lysosome with resultingabnormal storage of complex macromole-cules. When a lysosomal pathway is blocked,there is progressive accumulation of a vari-ety of partially degraded intermediate meta-bolic products such as triglycerides, sterols,sphingolipids, sulfatides, sphingomyelin,gangliosides, and lipofuscins (2). The in-creasing storage of substrates within lyso-somes results in impaired function of theaffected organs. The pathological features ofthe various LDs depend on the nature of thestored substrate and the organs where stor-age occurs. Substrate accumulation occursprimarily in the organs where they are syn-thesized (e.g., liver, spleen, bone, and ner-vous system). This explains in part the variedorgan involvement and symptomatology ofthese disorders. Defective targeting of lyso-somal enzymes to lysosomes (e.g., I-cell dis-ease), abnormal lysosomal membrane pro-teins (e.g., Danon disease), and defectiveegress of substrate (e.g., infantile sialic acidstorage disease/Salla disease) also may cause

abnormal storage. As the lysosomes enlarge,cellular and organ function are increasinglyimpaired. The exact causes of such impair-ment, however, are still the subject of inves-tigation. Because a wide range of clinicalfeatures are encountered in LDs, diseasepathogenesis presumably involves the acti-

vation of various deleterious biochemicalpathways or cellular processes. The releaseof acid hydrolases into the cytoplasm un-doubtedly could cause cellular damage, butsuch an occurrence has not been clearly es-tablished. In theory, defective transport ofsubstrates into and out of lysosomes second-ary to abnormal storage may play a role indisease pathogenesis, especially in disordersthat involve membrane lipids (e.g., sphingo-lipidoses). Dysregulation of apoptosis maycause disease manifestations in some LDs.Indeed, increased apoptosis has been notedin a number of the sphingolipidoses and inthe neuronal ceroid lipofuscinoses. Geneprofiling using microarrays has provided evi-dence for pathological microglial activationand subsequent reactive gliosis followingneuronal cell death in GM1and GM2gan-gliosidoses and mucopolysaccharidoses typesI and IIIB (6). These possible mechanismsof pathogenesis, of course, are not mutuallyexclusive, and various combinations may ex-ist in a given LD. All these disorders are inherited as autoso-mal recessive traits, with the notable excep-tions of Hunter syndrome (MPS-II), Fabrydisease, and Danon disease, which are X-linked conditions. There are more than 40LDs, and each is rare. In aggregate, the inci-dence of LDs is about 1 in 7000 to 1 in10,000 births (6). Each LD is caused by mu-tations in a specific gene. However, in mostcases, numerous mutations have been de-scribed in different patients affected by thesame condition. The prognosis usually can-not be determined on the basis of genotyp-ing, although exceptions exist. Certain eth-nic groups may show an increased prevalenceof a given condition. Examples include an

increased occurrence of Tay-Sachs diseaseGaucher disease type 1, Niemann-Pick disease type A, and mucolipidosis IV in the

Ashkenazi Jewish population and an increased frequency of infantile neuronal ceroid lipofuscinosis, Salla disease, and aspartylglucosaminuria in patients of Finnishdescent. In such instances of increased prevalence in an ethnic group, typically only afew mutations are responsible for causingdisease (7). Classification of LDs is based on the major type(s) of stored substances present in agiven condition. However, because lysosomal enzymes may degrade a variety of different substrates, resulting in a complex pattern of storage, in some cases classificationis not straightforward. Major categories oLD include the mucopolysaccharidosessphingolipidoses, oligosaccharidoses (glycoproteinoses), and neuronal ceroid lipofuscinoses. Select disorders from each of thesecategories are described below. A comprehensive list of LDs is shown in the corresponding tables.

MUCOPOLYSACCHARIDOSES

Etiology/Pathophysiology The mucopolysaccharides are a heterogeneous group omacromolecules involved predominantly inthe structural integrity of the extracellulamatrix. They consist of unbranched polysaccharide chains containing both acidic andamino sugars and are also referred to asglycosaminoglycans or, when linked to proteinsproteoglycans. There is varied tissue distribution for the different mucopolysaccharides: keratan sulfate is found predominantlin cartilage, cornea, and intervertebral disksdermatan sulfate is found in heart, bloodvessels, and skin; and heparan sulfate is acomponent of lung, arteries, and cell surfaces in general. Mucopolysaccharidoses (MPSs) are disorders resulting from defects in the stepwise

Lysosomal DisordersGregory M. Enns, MB, ChBRobert D. Steiner, MD

Tina M. Cowan, PhD, FACMG

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Part 9 | Select Disorders of Complex Molecule Biosynthesis722722

TYPES OF MUCOPOLYSACCHARIDOSE S OCCURRE NCE GENE LOCUS OMIM

Hurler syndrome (MPS-IH) ~1:100,000 IDUA 4p16.3 607014

Scheie syndrome (MPS-IS) ~1:1,000,000 IDUA 4p16.3 607016

Hurler-Scheie syndrome (MPS-IH/S) ~1:300,000 IDUA 4p16.3 607015

Hunter syndrome (MPS-II) ~1:100,000 IDS Xq28 309900

Sanfilippo syndrome type A (MPS-IIIA) ~1:130,000 SGSH 17q25.3 252900

Sanfilippo syndrome type B (MPS-IIIB) ~1:230,000 NAGLU 17q21 252920

Sanfilippo syndrome type C (MPS IIIC) ~1:1,400,000 Unknown 252930

Sanfilippo syndrome type D (MPS-IIID) ~1:1,000,000 GNS 12q14 252940

Morquio syndrome type A (MPS-IVA) ~1:200,000 GALNS 16q24.3 253000

Morquio syndrome type B (MPS-IVB) ~1:250,000 GLB1 3p21.33 230500

Maroteaux-Lamy syndrome (MPS-VI) ~1:200,000 ASB 5q11-q13 253200

Sly syndrome (MPS-VII) ~1:1,500,000 GUSB 7q21.11 253220

Hyaluronidase deficiency (MPS-IX) HYAL1 3p21 607071

CLINIC AL PRESE NTATIONFORM FINDI NGS Birth Childhood & Adolescence

Hurler syndrome (MPS-IH) curine dermatan and Most appear normal, Coarsening of features, hepato- heparan sulfate; but hydrops fetalis splenomegaly, corneal clouding

T-L-iduronidase activity may occur develops in infancy and progress; skeletal abnormalities (dysostosis multiplex),

joint limitation, and short stature develop in childhood; progressive mental retardation occurs

Scheie syndrome (MPS-IS) Same as MPS IH Appear normal Only mild systemic features occur; intelligence, lifespan, and stature are normal

HurlerScheie syndrome Same as MPS IH Appear normal Features intermediate between MPS-IH(MPS-IH/S) and MPS-IS

Hunter syndrome (MPS-II) curine dermatan and Appear normal Features are similar to MPS I, except that heparan sulfate; there is no corneal clouding and skin Tiduronate sulfatase activity can appear pebbly

Mucopolysaccharidoses

AT-A-GLANCELysosomal Disorders

Lysosomal disorders (LDs) are a heterogeneousgroup of over 40 inherited disorders that individu-ally are rare but as a group have an incidence of 1in 7000 to 1 in 10,000 live births. LDs are caused byenzyme, enzyme activator, membrane transporter,or membrane protein defects that result in abnormal

accumulation of complex macromolecules normallydegraded in lysosomes. Multisystemic involvementand progressive disease are typical, although somedisorders affect primarily a single organ system (e.g.,skeletal or central nervous system). The extent andseverity of the manifestations depend on the type and

amount of substrate that accumulates. For most of theseconditions, treatment is supportive. Enzyme-replacementtherapy (ERT) and bone-marrow transplantation (BMT)have been successful in some LDs. Novel therapies in-clude substrate-reduction therapy (SRT) by small mol-ecules that can cross the bloodbrain barrier (3, 4).

The mucopolysaccharidoses are lysosomal storagedisorders characterized by deficient degradation ofmucopolysaccharides (glycosaminoglycans). Storagematerial consists of dermatan sulfate, heparan sulfate,

keratan sulfate, chondroitin sulfate, or hyaluronan ei-ther in isolation or in various combinations depend-

ing on the underlying enzymatic defect. These con-ditions typically are multisystemic, with progressiveinvolvement of the brain, visceral organs, and bone.Mental retardation is common, although not invari-

able. ERT has become avaliable for Hurler syndrome(MPS-IH), although efficacy has been limited because

of the inability of the recombinant enzyme to crossthe bloodbrain barrier. BMT has been successful inaltering the course of some of these disorders but isnot curative. The pattern of pathological glycosami-

noglycans in the various mucopolysaccharidoses aresummarized below.


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Lysosomal Disorders

CLINIC AL PRESE NTATIONFORM FIND INGS Birth Childhood & Adolescence

Sanfilippo syndrome curine heparan sulfate; Appear normal Coarse features and relatively mild(MPS-IIIA) TheparanN-sulfatase activity organomegaly occur in early childhood; progressive mental retardation and behavior problems occur in childhood

Sanfilippo syndrome curine heparan sulfate;

(MPS-IIIB) T-N-acetylglucosaminidase activity

Sanfilippo syndrome curine heparan sulfate(MPS-IIIC) Tacetyl Co-A: -glucosaminidine acetyltransferase activity

Sanfilippo syndrome curine heparan sulfate;(MPS-IIID) TN-acetylglucosamine- 6-sulfatase activity

Morquio syndrome type A curine keratan and Most appear normal, Intelligence is normal; mild to severe skeletal(MPS-IVA) chondroitin 6-sulfate; but hydrops fetalis manifestations are present; corneal clounding TN-acetylgalactosamine- may occur and hearing impairment are common 6-sulfatase activity

Morquio syndrome type Bc

urine keratan and(MPS-IVB) chondroitin 6-sulfate; T-galactosidase activity

Maroteaux-Lamy syndrome curine dermatan sulfate; Appear normal Intelligence is normal; skeletal manifestations(MPS-VI) TN-acetylgalactosamine- are prominent and noticed at 624 months; 4-sulfatase activity corneal clouding, valvular heart disease, and (arylsulfatase B) spinal cord compression occur

Sly syndrome (MPS-VII) curine dermatan, heparan, Most appear normal, Coarse features, organomegaly and and chondroitin 6-sulfate; but hydrops fetalis dysostosis multiplex are typical although T-glucuronidase activity may occur and severity are variable

Hyaluronidase deficiency Thyaluronidase activity Only one patient described; intelligence is normal; short stature(MPS-IX) and nodular periarticular masses are present

TYPES OF LOCALIZATION DEFECTS OCCURRE NCE GENE LOCUS OMIM

I-cell disease (mucolipidosis II) ~1:325,000 GNPTA 4q21-q23 607840

Pseudo-Hurler polydystrophy GNPTA 4q21-q23 252600

(mucolipidosis III)


I-cell disease Normal urine mucopolysaccarides, Features may present Similar to MPS-IH, except coarse facies may be(mucolipidosis I I) vacuolated lymphocytes, at birth; hydrops present at birth and this condition is more TN-acetylglucosamine- fetalis may occur rapidly progressive 1-transferase activity

Pseudo-Hurler polydystrophy Appear normal More mild than I-cell disease; finger contractures,(mucolipidosis II I) scoliosis, and short stature is present in childhood; a progressive skeletal dysplasia is typical; 50% have learning disabilities or mental retardation

Disorders of Lysosomal Enzyme LocalizationI-cell disease (mucolipidosis II) and pseudo-Hurlerpolydystrophy (mucolipidosis III) are both causedby defective targeting of lysosomal enzymes to ly-

of I-cell disease resemble those of Hurler syndromealthough onset is earlier. Pseudo-Hurler polydystrophy has a milder course.

sosomes. Newly synthesized lysosomal enzymes aretherefore secreted into the extracellular matrix in-stead of localizing to lysosomes. The clinical features


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TYPES OF SPHINGOLIPIDOSES OCCURRENCE GENE LOCUS OMIM

GM2-gangliosidoses Type A (TaySachs disease)* ~1:200,000 HEXA 15q23-q24 272800 Type O (Sandhoff disease) ~1:400,000 HEXB 5q13 268800 Type AB (GM2-activator deficiency) GM2A 5q31-q33 272750

NiemannPick disease type A* ~1:250,000 SMPD1 11p15 275200

NeimannPick disease type B* SMPD1 11p15 607608

NiemannPick disease type C ~1:200,000 NPC1 18q11-q12 257220 NPC2 14q24.3 607625

Gaucher disease type 1* ~1:60,000 GBA 1q21 230800

Gaucher disease type 2 GBA 1q21 230900

Gaucher disease type 3 GBA 1q21 231000

Fabry disease ~1:120,000 GLA Xq22 301500

Metachromatic leukodystrophy ~1:100,000 ARSA 22q13 250100

Saposin B deficiency PSAP 10q22 249900

Multiple sulfatase deficiency ~1:1,400,000 SUMF1 3p26 272200

Globoid cell leukodystrophy (Krabbe disease) ~1:150,000 GALC 14q31 245200

GM1-gangliosidosis type I*** GLB1 3p21.33 230500

GM1-gangliosidosis type II GLB1 3p21.33 230600

GM1-gangliosidosis type III GLB1 3p21.33 230560

Farber lipogranulomatosis ASAH 8p22-p21 228000

*Higher incidence in Ashkenazi Jewish population; ***Combined estimated incidence of approx. 1/100,0001/300,000.


TaySachs disease T-hexosaminidase A activity Appear normal Rapidly progressive neuro-degeneration,an exaggerated startle reflex, and a cherry redspot are typical; late- and adult-onset forms occur

Sandhoff disease curine oligosaccharides; Appear normal Similar to TaySachs disease T-hexosaminidase A & B activity

GM2-activator deficiency TGM2activator Appear normal Similar to TaySachs disease(AB variant)

NiemannPick disease Tsphingomyelinase activity Most appear normal, Hepatosplenomegaly develops in infancy;type A but hydrops rapid neurodegeneration occurs; 50% have a fetalis may occur cherry red spot

NiemannPick disease Tsphingomyelinase activity Appear normal Splenomegaly often noted; hepatomegalytype B and pulmonary involvement are typical; normal intelligence; hyperlipidemia is common

Niemann-Pick Disease Tcholesterol esterification Neonatal hepatitis Clinical features include hepatosplenomegaly,Type C may occur (which can be a mild and late finding), upward gaze palsy, developmental regression, seizures (rare), and ataxia

SphingolipidosesThe sphingolipidoses are characterized by abnor-mal storage of complex phospholipids that containa sphingosine moiety. Sphingolipids are essentialcomponents of the cell membrane and are con-

stantly being recycled. Although central nervous sys-tem involvement, with developmental regression, ispresent in many of these conditions, some featureonly systemic involvement. ERT for Gaucher disease

type 1 and Fabry disease has revolutionized the careof these individuals. Unfortunately, for most of thesphingolipidoses, therapy is supportive.


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Gaucher disease type 1 T-glucosidase activity Appear normal Splenomegaly may appear, but some remain asymptomatic; avascular necrosis of the hip and growth retardation may occur

Gaucher disease type 2 T-glucosidase activity Hydrops fetalis and Neurodegeneration and hepatosplenomegaly occur ichthyosis may occur in infancy or earlychildhood

Gaucher disease type 3 T-glucosidase activity Appear normal Intermediate between types 1 and 2

Fabry disease T-galactosidase activity Appear normal Extremity pain and paresthesias common in childhood; asymptomatic corneal opacities and heart disease occur; renal failure in adulthood

Metachromatic curine sulfatides Appear normal Progressive neurodegeneration, withoutleukodystrophy Tarylsulfatase A activity organomegaly, occurs; late-infantile, juvenile, and adult forms exist

Saposin B deficiency curine sulfatides Appear normal Similar to metachromatic leukodystrophy Tsulfatide activator protein

Multiple sulfatase curine mucopolysaccharides Hydrops fetalis Clinical features resemble variousdeficiency and oligosaccharides; may occur combinations characteristic of single sulfatase

Tarylsulfatase A, B, & C activities; deficiencies, ranging from MPS-IH-like to Tsulfamidase activity; metachromatic leukodystrophy-like Tiduronate-2-sulfatase activity

Krabbe disease T-galactocerebroside activity Appear normal Progressive neurodegeneration without organomegaly occurs

GM1gangliosidosis curine oligosaccharides Most appear normal, Neurodegeneration, coarse features. Type I: infantile Nl or slightly curine but hydrops hypotonia, hepatosplenomegaly, dysostosis multiplex, mucopolysaccharides fetalis may occur and cherry red spots (50%); infants to adults T-Galactosidase present with ataxia, dystonia, normal intelligence,

or mental retardation

Farber lipogranulomatosis Tacid ceramidase acitivity Appear normal Typically presents in infancy with painful, deformed joints, subcutaneous nodules, and progressive

hoarseness; visceral and neurologic involvementis variable

TYPES OF SIALIC ACID DISORDERS OCCURRENCE GENE LOCUS OMIM

Sialidosis (Mucolipidosis I) ~1:4,000,000 NEU1 6p21.3 256550

Galactosialidosis PPGB 20q13 256540

Infantile sialic acid storage disease ~1:500,000 SLC17A5 6q14-q15 269920

Salla disease* SLC17A5 6q14-q15 604369

Sialuria GNE 9q12-p11 269921

*Higher incidence in Finnish population.

Sialic Acid DisordersSialic acid disorders are a heterogeneous group ofconditions characterized by abnormal accumulationofN-acetyl-neuraminic acid (sialic acid) in lysosomesor the cytoplasm (sialuria). The biochemical defectsand clinical phenotypes differ in each condition.

Sialidosis is caused by neuraminidase deficiency.Galactosialidosis is associated with combined defi-

ciency of -galactosidase and neuraminidase second-ary to a defect in lysosomal protective protein/cathep-sin A. Infantile free sialic acid storage disease and Salladisease are caused by defective lysosomal membranetransport of sialic acid and other acidic monosaccha-

rides. Sialuria has been described in only a handfulof patients and is caused by impaired feedback in-

hibition of uridine diphosphate-N-acetylglucosamine2-epimerase. Sialuria is inherited in an autosomadominant fashion (the other conditions listed herare autosomal recessive). These condtions havea variable clinical phenotype, ranging from being

similar to MPS-IH to isolated central nervous systeminvolvement.


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Sialidosis Tneuraminidase activity Most appear normal, Variable features occur, ranging from MPS-IH-(Mucolipidosis I) but hydrops fetalis like to development of a cherry red spot may occur and myoclonus in adolescence

Galactosialidosis curine sialic acid- Most appear normal, Coarse facial features, dysostosis multiplex containing oligosaccharides; but hydrops fetalis and cherry red spots

Tneuraminidase activity; may occur T-galactosidase activity

Infantile sialic acid curine sialic acid Hydrops fetalis may occur Coarse features, profound mental retardation,storage disease and hepatosplenomegaly occur in infancy

Salla disease curine sialic acid Most appear normal, Ataxia and mental retardation occur in childhood; but hydrops fetalis may occur high incidence in Finland

Sialuria curine sialic acid Appear normal Coarse features, hepatosplenomegaly, and relatively mild intellectual involvement occur (sialic acid accumulates in the cytoplasm in this condition)

TYPES OF OLIGOSACCHARIDOSES OCCURRENCE GENE LOCUS OMIM

GM1-gangliosidosis type I*** GLB1 3p21.33 230500

GM1-gangliosidosis type II GLB1 3p21.33 230600

GM1-gangliosidosis type III GLB1 3p21.33 230560

GM2-gangliosidoses

Type A (TaySachs disease)* ~1:200,000 HEXA 15q23-q24 272800

Type O (Sandhoff disease) ~1:400,000 HEXB 5q13 268800 Type AB (GM2-activator deficiency) GM2A 5q31-q33 272750

-Mannosidosis ~1:1,000,000 MAN2B1 19cen-q12 248500

-Mannosidosis MANBA 4q22-q25 248510

Fucosidosis FUCA1 1p34 230000

Sialidosis (mucolipidosis I) ~1:4,000,000 NEU1 6p21.3 256550

Galactosialidosis PPGB 20q13 2 56540

Schindler disease NAGA 22q11 104170

Aspartylglucosaminuria* ~1:2,000,000 AGA 4q32-q33 208400

*Higher incidence in Finnish population; ***Combined estimated incidence of approx. 1/100,0001/300,000.

Oligosaccharidoses are characterized by abnormal ly-sosomal storage of complex glycoproteins. Some ofthese disorders resemble classical mucopolysacchari-

doses (e.g., -mannosidosis, fucosidosis), whereasothers primarily affect the central nervous system,

similar to many sphingolipidoses (e.g., Schindler dis-ease, aspartylglucosaminuria).

Oligosaccharidoses (glycoproteinoses)


GM1-gangliosidosis curine oligosaccharides, Most appear normal, Neurodegeneration, coarse features. Type I: Nl c urine mucopolysaccharides, but hydrops fetalis infantile hypotonia, hepatosplenomegaly, T-galactosidase may occur dysostosis multiplex, and cherry red spots (50%); infants to adults present with ataxia, dystonia, normal intelligence, or mental retardation

TaySachs disease T-hexosaminidase A activity Appear normal Rapidly progressive neurodegeneration, an exaggerated startle reflex, and a cherry red spot are typical


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Lysosomal Disorders


Sandhoff disease curine oligosaccharides; Appear normal Similar to TaySachs disease T-hexosaminidase A & B activity

GM2-activator deficiency TGM2activator Appear normal Similar to TaySachs disease(AB variant)

-Mannosidosis curine oligosaccharides Appear normal Infantile MPS-IH-like, and milder T-mannosidase activity juvenile/adult forms exist

-Mannosidosis curine oligosaccharides; Appear normal Variable features, ranging from T-mannosidase activity infantile neurodegeneration to juvenile mental retardation; hearing loss, and angiokeratoma, may occur

Fucosidosis csweat sodium chloride; Appear normal Infantile MPS-IH-like, and milder juvenile curine oligosaccharides; and adult forms exist; angiokeratomas

T-L-fucosidase are relatively common

Sialidosis Tneuraminidase activity Most appear normal, Variable features occur, ranging(mucolipidosis I) but hydrops fetalis from MPS-IH-like to development may occur of a cherry red spot; myoclonus in adolescence

Galactosialidosis curine sialic acid-containing Most appear normal, Coarse facial features, dysostosis oligosaccharides; but hydrops fetalis multiplex and cherry red spots. Tneuraminidase activity; may occur T-galactosidase activity

Schindler disease curine oligosaccharides Appear normal Variable features ranging from infantile T-N-acetylgalactos- neuraxonal dystrophy to mild impairment; aminidase activity angiokeratomas and mild intellectual impairment occur in an adult form

Aspartylglucosaminuria curine glycoasparigines; Appear normal Progressive neurodegeneration occurs Taspartylglucos- from age 24 years; connective tissue aminidase activity changes lead to coarse features, thick calvarium, and osteoporosis

TYPES OF NCL OCCURRENCE GENE LOCUS OMIM

Infantile NCL (Santavuori-Haltia disease)* 1:13,000 PPT1 1p32 256730

Late infantile NCL ~1/100,000 CLN2 11p15.5 204500(Jansky-Bielschowshy disease)

Juvenile NCL (Batten disease) ~1:170,000 CLN3 16p12.1 204200

Adult NCL (Kufs disease) PPT1 1p32 204300 CLN3, CLN4 16p12.1

*Higher incidence in Finnish population.

Neuronal Ceroid LipofuscinosesNeuronal ceroid lipofuscinoses (NCL) are severe,progressive neurodegenerative conditions that fea-ture the accumulation of an autofluorescent waxy

pigment (lipofuscin) in the lysosomes. These condi-tions may have onset anytime from infancy throughadulthood. Typical features include developmental

arrest and regression, microcephaly, blindness, andseizures.


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OTHER LYSOSOMALSTORAGE DISORDERS OCCURRENCE GENE LOCUS OMIM

Wolman disease ~1:530,000 LIPA 10q24-q25 278000

Cholesteryl ester storage disease LIPA 10q24-q25 278000

Cystinosis (see Chapter 42) ~1:200,000 CTNS 17p13 219800

Pycnodysostosis CTSK 1q21 265800

Pompe disease ~1:150,000 GAA 17q25 232300(glycogen storage disease type II)

Danon disease LAMP2 Xq24 300257

Mucolipidosis IV MCOLN1 19p13 252650

Other Lysosomal Storage DisordersThere are a number of other lysosomal disorders thatare more difficult to classify into a specific category

on the basis of the type of material stored. These arelisted below.


Wolman disease Nl plasma cholesterol Hydrops fetalis; is typical Neonates have increased vomiting and and triglycerides; onset hepatosplenomegaly diarrhea; anemia; abnormal development; Tacid lipase activity is typical calcification of adrenal glands; death usually by age 6 months

Cholesteryl ester cplasma cholesterol Hepatomegaly Onset varies from birth to second decade;storage disease + triglycerides; may be present progressive hepatomegaly; neurologic Tacid lipase activity involvement and adrenal calcification are rare

Cystinosis Aminoaciduria, proteinuria, glycosuria; Appearnormal Infantspresentwithvomiting, failure to(see Chapter 42) TK, TPO4

2, thrive, and polyuria; crystal keratopathy

Turic acid and hypothyroidism occur;milder variants present later

Pycnodysostosis Tcathepsin K activity May have dysmorphic Short stature, dysmorphic features,features osteosclerosis, and fractures

Pompe disease Tacid maltase activity Appear normal Cardiomegaly, hepatomegaly, hypotonia and weakness in early infancy; late-onset forms

with skeletal muscle involvement andrespiratory distress

Danon disease Tlysosomal associated Appear normal May appear in infancy with cardiomyopathy membrane protein 2 and myopathy; but typically presents (LAMP-2) in second decade

Mucolipidosis IV Nlurine mucopolysaccharides Appearnormal Mentalretardation, retinaldegeneration, mucopolysaccharides and corneal clouding

CLINIC AL PRES ENTATIONFORM FIND INGS Birth Childhood & Adolescence

Infantile NCL Normal blood and urinestudies; Appear normal Progressive neurodegeneration andmacular(Santavuori-Haltia disease) Tpalmitoyl-protein thioesterase activity degenerationoccur; death in childhood is typical

Late infantile NCL Normalblood and urinestudies; Appearnormal Slowerprogressionthaninfantile NCL;(Jansky-Bielschowshy disease) Tpepsinase activity deathoccursbetween 1015 years

Juvenile NCL (Batten disease) Normalroutinebloodand Appearnormal Neurologicandopthalmologic features in late child- urine studies hood; death between 20 and 40 years is typical


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Lysosomal Disorders

degradation of mucopolysaccharides due toenzymatic blocks at various points in the cat-abolic pathways of keratan, heparan, and der-

matan sulfate and hyaluronan. There are 11different known enzyme deficiencies leadingto abnormal mucopolysaccharide storage, in-cluding four genetically distinct deficienciesleading to Sanfilippo syndrome and two lead-ing to Morquio syndrome. All the MPSs areinherited in an autosomal recessive mannerexcept Hunter syndrome (MPS-II), which is

X-linked. In the current MPS classificationscheme, MPS-V (formerly Scheie syndrome)and MPS-VIII are no longer recognized. Rep-resentative structures of the three major ab-normally stored mucopolysaccharideskeratan sulfate, dermatan sulfate, and heparan

sulfateare shown in Figure 43-1. Abnormal mucopolysaccharide storageleads to a variety of pathophysiological changesthroughout the body. Somatic storage resultsin variable organomegaly (e.g., hepatomegalyand splenomegaly), coarsening of facial fea-tures, cardiac abnormalities (e.g., cardiomy-opathy, valvular regurgitation, and narrowingof the coronary arteries), joint stiffness, pro-gressive airway obstruction, hearing loss, cor-neal clouding leading to blindness, and shortstature. Typical skeletal abnormalities, knownas dysostosis multiplex, include vertebral

beaking, proximal pointing of the metacarpals,and the so-called J-shaped sella apparent onlateral skull x-ray.

Histological changes associated with theMPSs include large, empty-appearing vacu-oles (Figure 43-2), inclusions resembling ze-bra bodies, and metachromatic granules(seen on staining with a cationic dye such as

Alcian blue) representing lysosomes dis-tended by stored material. Storage is seen inmany cell types, including mononuclear

phagocytic cells, endothelial cells, intimasmooth muscle cells, and fibroblasts. Depending on the specific disorder and the presence or absence of residual enzyme activitystorage also may be seen in other specializedcells, including hepatocytes and neuronsThe definitive diagnosis is based on enzymeassays for the specific lysosomal enzymes and

demonstration of deficient or significantly reduced (10% of normal) enzyme activity. Assays can be performed using either leukocyteor cultured skin fibroblasts. More recentlythe activities of several lysosomal enzymesincluding -iduronidase and -glucosidasehave been reliably measured using driedblood spots (8), raising the possibility of presymptomatic screening for these disorders inthe near future.

Clinical Presentation Although clinically heterogeneous, the MPSs generally are characterized by a period of normal growth and de

velopment, followed by progressiveorganomegaly (including hepatomegaly andsplenomegaly), developmental delay in manyof the disorders, skeletal abnormalities (dysostosis multiplex), and coarsening of facial features (9). Depending on the type and severityof the disorder, the age of presentation rangefrom late infancy to adulthood. Other characteristic features include umbilical herniagibbus deformity, and short statureDistinguishing features of each of the MPSare summarized below.

MPS-I (Hurler, Hurler/Scheie,

Scheie Syndromes; MPS-IH,MPS-IH/S, MPS-IS)Type I MPSs encompass a wide phenotypicspectrum ranging from severe (Hurler syndrome) to mild (Scheie syndrome). Despitethis clinical variability, all cases of MPS-I arcaused by deficient activity of -iduronidase(IDUA), which normally cleaves iduronateresidues from dermatan sulfate and heparansulfate. Deficient IDUA activity leads to abnormal storage of dermatan and heparan sulfatein multiple organs and tissues, including liverspleen, connective tissue, and brain, as welas to abnormal urinary excretion of these

compounds. More than 70 different IDUAmutations have been described to date (10)Those associated with the more severe Hurlephenotype are predominately nonsense mutations leading to a complete absence of enzymeactivity, whereas those underlying milder phenotypes are often single-base substitutionsThe distinction between Hurler, Scheie, andthe intermediate phenotypes cannot be madeby biochemical studies because all such patients excrete abnormal levels of dermatanand heparan sulfate, and all have similarlydeficient IDUA activity when measured by

Galactose Glucose Iduronic acid Glucuronic acid

S

o o

o

NAc

SSS

NAc

keratan

sulfate:

1

2

3 4

S-O

S

o

o

o

NAc

dermatan

sulfate:

5

6

7 4 8

SS

o

S N-HN-S

o

o o

AcCo A

S

heparansulfate:

56

9 10

83

12

11

FIGURE 43-1.Representative structures of keratan sulfate, dermatan sulfate, and heparan sulfate. Numbers indicatingspecific enzymes and their corresponding disease states are 1) galactose-6-sulfatase (Morquio syndrome type A),

2) -galactosidase (Morquio syndrome type B), 3) N-acetylglucosamine-6-sulfatase (Sanfilippo syndrome type D),

4) -hexosaminidase A and B (Sandhoff disease), 5) iduronate sulfatase (Hunter syndrome), 6)-iduronidase (Hurler,

Scheie syndromes), 7)N-acetylgalactosamine-4-sulfatase (MaroteauxLamy syndrome), 8) -glucuronidase (Sly syndrome),

9) heparan-N-sulfatase (Sanfilippo syndrome type A), 10) glucuronate sulfatase (disease unknown), 11) -acetyl-CoA:-

glucosaminide acetyltransferase (Sanfilippo syndrome type C), 12) -N-acetylglucosaminidase (Sanfilippo syndrome type B).

FIGURE 43-2.Abnormal lysosomal storage in amacrophage of a patient with Hurler syndrome. (Courtesy

of Richard Sibley, M.D., Stanford University Pathology

Department.)


12/38


typical laboratory assays employing an artifi-cial enzyme substrate. Patients with Hurler syndrome present earlyand with classical features of an MPS, includ-ing hepatosplenomegaly, coarse facial features,dysostosis multiplex, and developmental delay(9) (Figure 43-3).

Patients often appear normal

at birth but may have inguinal hernias. Hurlersyndrome is often first suspected by the childsfacial appearance, including coarsening of fea-tures and an enlarged tongue, with develop-mental delay apparent during the first year.Development may reach the functional levelof a 2- to 4-year-old, followed by rapid decline

and loss of milestones. Other features includerecurrent ear and nose infections, short stat-ure, cardiomyopathy, and communicating hy-drocephalus with increased intracranial pres-sure, with death typically occurring in the firstdecade. At the other end of the spectrum,patients with Scheie syndrome typically are

A

D

G

I

C

F

B

H

E

FIGURE 43-3.Hurler syndrome (MPS-IH). A to E. Examplesof characteristic facies in Hurler syndrome (macrocephalic

head with frontal bossing and scaphocephaly, flat face with

coarse features, wide-set prominent eyes, full lips, protruding

tongue, open mouth, flared nostrils, low nasal bridge, bushy

eyebrows, thickened-coarse hair, and low set hairline).

F to G. Clawhand deformity. H.Pelvic characteristics of Hurler

syndrome (basilar portion of ilia, flared iliac crest, long femoral

neck, and cox valga) in an 8-year-old patient. I.Close-up

photo of the cloudy ornea feature found in Hurler syndrome.

(Courtesy of Robert Gorlin, D.D.S, M.S., D.Sc., University of

Minnesota Medial School.)


13/38

Lysosomal Disorders

diagnosed in the second decade of life, withsymptoms appearing after the age of 5 years.Symptoms include joint stiffness, mild claw-hand deformity, visual impairment due to cor-

neal clouding, and a broadened or mildlycoarse facial appearance (Figure 43-5). Othercomplications can include carpal tunnelsyndrome, aortic valve disease, and deafness.Intelligence and lifespan are both characteris-tically normal in Scheie syndrome. Finally,Hurler/Scheie syndrome (MPS-IH/S) is usedto describe an intermediate phenotype be-tween the two extremes, including later age ofonset and slower rate of progression thanHurler syndrome (Figure 43-4). Intelligence isnormal or only mildly impaired, and survival isinto adulthood.

Hunter Syndrome (MPS-II)Hunter syndrome is the only MPS that is X-linked and results from deficient activity of

iduronate-2-sulfatase (IDS), the enzyme thatnormally cleaves sulfate residues from thenumber 2 position of iduronate in the deg-radation of dermatan sulfate and heparansulfate (see Figure 43-1). As with MPS-I, de-ficient IDS activity leads to abnormal storageof dermatan and heparan sulfate in multipleorgans and tissues, including liver, spleen,connective tissue, and brain, as well as toabnormal urinary excretion of these com-pounds. The incidence of Hunter syndromehas been estimated at between 1 in 34,000and 1 in 165,000 male births in various popu-

lations. Over 270 IDS mutations have beenidentified, many of which represent complegene rearrangements (11). This vast spectrum of mutations underlies the wide clinica

variability described in patients with Huntesyndrome. As an X-linked recessive disorder, Huntesyndrome typically occurs only in malesHowever, rare females have been reportedwith Hunter syndrome resulting fromnonrandom lyonization and preferentiainactivation of the nonmutant X chromosome (12). Hunter syndrome historically is dividedinto two discrete clinical entities, severe andmild, although the clinical phenotype ibest represented as a continuum between

A B D

C

E

FIGURE 43-4.Hurler-Scheie phenotype (MPS-IH/S) is

intermittent between Hurler and Scheie with the following

characteristics: macrocephaly, low nasal bridge, prominent

lips, micrognathia, mild to moderate claw-hand deformity,

joint limitation without gibbus (A to D),and corneal

clouding (E).


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these extremes. Patients appear normal atbirth, with the most severely affected males

presenting between 2 and 4 years of agewith coarsening of facial features, hepato-splenomegaly, short stature, joint stiffness,and progressive mental retardation. Persis-tent, asymptomatic skin lesions consistingof firm, hypopigmented papules on theback, chest, arms, and legs are also seen(13) (Figure 43-6). Corneas are characteris-tically clear, a feature that distinguishesHunter syndrome from Hurler syndrome.In addition, disease progression tends to beslower than in Hurler syndrome. Patientswith milder forms of Hunter syndrome mayhave normal intelligence and survival into

adulthood, with somatic involvement simi-lar to, but milder than, patients with moresevere forms of the disorder.

MPS-IIIA, -B, -C, and -D(Sanfilippo Syndrome Types A, B,C, and D)Sanfilippo syndrome results from a deficiencyin one of the four different heparan sulfatedegrading enzymes, heparan-N-sulfatase(type A), -N-acetylglucosaminidase (type B),acetyl coenzyme-A:-glucosaminidine acetyl-

transferase (type C), and N-acetylglucos-amine-6-sulfatase (type D). The combined

incidence of Sanfilippo syndrome has beenestimated at 1 in 58,000 live births (14),with types A and B being the most commonand type D being extremely rare (15). Alltypes of Sanfilippo syndrome are associatedwith abnormal storage of heparan sulfate,predominantly affecting the central nervoussystem (CNS). Patients typically presentaround 36 years of age with severe behav-ioral abnormalities, including hyperactivityand aggression, developmental delay, andmental retardation. In contrast to Hurlerand Hunter syndromes, somatic findingsare relatively mild and include little or no

hepatosplenomegaly or claw-hand defor-mity, only mild skeletal abnormalities, andclear corneas. Hirsutism is often present,including coarse, thick hair and synophrys(Figure 43-7). In particular, type B isassociated with a more severe course, in-cluding earlier onset and more pronouncedneurological abnormalities than the otherforms of the disorder (15). In addition toSanfilippo syndrome, deviant, aggressivebehavior is also prominent in patientswith MPS-II (Hunter syndrome) and-fucosidosis.

Morquio Syndrome(MPS-IVA and -B)Morquio syndrome results from a deficiencyin one of the two keratan sulfatedegradingenzymes, N-acetylgalactosamine-6-sulfatase(GALNS, MPS-IVA) and -galactosidase(MPS-IVB). It is interesting to note that -galactosidase is also the enzyme deficientin the sphingolipidosis GM1-gangliosidosisdue to the effects of different mutations ontwo sites with distinct substrate specificities(keratan sulfate and GM1-ganglioside) of thesame enzyme (16). A deficiency of either GALNS or -galacto-sidase leads to abnormal storage of keratan

sulfate and its abnormal excretion in theurine. Because keratan sulfate is a componentof cartilage, the disease predominately affectsthe skeletal system, leaving other tissues andthe CNS relatively spared. Typical featuresinclude dwarfism with short trunk, scoliosis,and vertebral deformities, becoming apparentbetween 1 and 4 years of age and worseningover time (Figure 43-8). Odontoid hypoplasiais a universal finding and can lead to life-threatening atlantoaxial instability. Both mildand severe forms of both MPS-IVA and MPS-IVB have been described (17).

FIGURE 43-5.Characteristics of Scheie syndrome: broadened but milder coarse facial appearance (figures a,b) and mild claw hand deformity (figure c). (Courtesy of Robert Gorlin, D.D.S,

M.S., D.Sc., University of Minnesota Medical School).

A B C


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Lysosomal Disorders

A B

D

C

E

FIGURE 43-6.Characteristics of Hunter syndrome

(MPS-II). While similarly enlarged head and coarse facies to

MPS-IH, Hunter patients (MPS-II) bear more resemblance

to family members than Hurler patients. Features include

flat nose, depressed nasal bridge, enlarged tongue, and low

hairline (A to D).Hunter patients do not have cornealclouding or gibbus. E. Claw-hand deformity with broad and

stubby fingers. (Courtesy of Susan Berry, M.D., University o

Minnesota Medical School.)

FIGURE 43-7.Characteristics of Sanfilippo syndrome (MPS-III). Mildly coarse facies with a slightly depressed nasal bridge

and thickened lips, bushy eyebrows. Normal corneas. (Courtesy of Susan Berry, M.D., and Robert Gorlin, D.D.S, M.S., D.Sc.,

University of Minnesota Medical School.)

A B

MaroteauxLamy Syndrome(MPS-VI)MaroteauxLamy syndrome is caused by adeficiency of N-acetylgalactosamine-4-sulfa-tase, also known as arylsulfatase B (ARSB)This enzyme is involved in the degradation o

dermatan sulfate, which has a wide tissue distribution but is not a component of the CNS

Accordingly, patients with MaroteauxLamysyndrome have a Hurler-like appearance buare distinguished by normal intelligence andlack of excretion of heparan sulfate. As withthe other MPSs, a number of different molecular mutations in the ARSB gene underliea broad range of clinical phenotypes rangingfrom severe to near normal (1820). Thepopulation frequency of MaroteauxLamysyndrome has been estimated at 1 in 248,000live births in Australia (21).


16/38


A

B

FIGURE 43-8.Characteristics of Morquio syndrome

(MPS-IV). The most characteristic features of Morquio syn-

drome are the skeletal features. A to D. Reduced heightdue to shortened neck and trunk; pectus carinatum; joint

laxity with enlarged wrists, marked kyphoscoliosis; thora-

columbar gibbus. E. The humerus, radius, ulna, and meta-

carpals are short, coarse, curved, and irregularly tabulated.

(Courtesy of Susan Berry, M.D., and Robert Gorlin, D.D.S,

M.S., D.Sc., University of Minnesota Medical School.)

C

E

D


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Lysosomal Disorders

Severely affected patients present in thefirst few years of life with growth delay, pro-gressive joint restriction, coarse facial fea-tures, hepatosplenomegaly, and cornealclouding (Figure 43-9). Skeletal abnormali-ties, including short stature and a constella-tion of deformities known as dysostosis mul-tiplex, are also characteristic. Cardiac

abnormalities include aortic and mitral val-vular dysfunction, resulting from abnormalaccumulations of glycosaminoglycans, aswell as cardiomyopathy. In severely affectedpatients, cardiac failure leads to death inthe second or third decade. Recently, an

adult patient was described with an attenu-ated phenotype of MaroteauxLamy syn-drome involving abnormal inclusion bodiesin leukocytes and mild hearing loss but nor-mal height, joint mobility, and facial ap-pearance, as well as normal findings onopthalomogical, cardiac, and skeletalexamination (20).

Sly Syndrome (MPS-VII)Sly syndrome is an extremely rare MPScaused by deficient activity of -glucuroni-dase (GUSB), which normally cleaves gluc-

uronide residues from dermatan sulfate, heparan sulfate, and chondroitin sulfate. Over 45different mutations in the GUSB gene havebeen reported, the majority of which arepoint mutations (22). Although first described in a 2-year-old bowith Hurler-like features (23), Sly syndromeis now recognized as having a wide pheno

typic spectrum. In its most severe form, it idistinguished from the other MPSs by havinga neonatal, or even fetal, age of onset. Thiform is characterized by dysostosis multiplexhepatosplenomegaly, and coarse facial features sometimes apparent even at birth. Feta

A

C

B

D

FIGURE 43-9.Characteristics of MaroteauxLamysyndrome (MPS-VI). Similar but milder coarse facies than

patients with Hurler syndrome (low nasal bridge, hyper-

telorism, full cheek and lips, bushy eyebrows), patients

with MaroteauxLamy may present with shor t stature,

protruding abdomen, and hepatosplenomegaly. (Courtesy

of Susan Berry, M.D., and Robert Gorlin, D.D.S, M.S., D.Sc.

University of Minnesota Medical School.)


18/38


death from nonimmune hydrops fetalis hasbeen reported in a number of patients (24).Milder patients have been described, includ-ing a child diagnosed at age 7 years with mildfacial dysmorphism, short stature, cornealopacity, and mild mental retardation. Thispatient died suddenly at age 37 years frompresumed cardiac arrest and represents the

longest known survivor of Sly syndrome (25).

Hyaluronidase Deficiency(MPS-IX)Hyaluronidase deficiency leads to the abnor-mal storage of hyaluronan (HA), a glycosami-noglycan of repeating disaccharide units ofglucuronic acid and N-acetylglucosamine. Itis abundant in extracellular matrix of connec-tive tissue, particularly in synovial fluid andvitreous humor. The gene encoding hyal-uronidase, HYAL1, is a member of a tandemlydistributed family of genes encoding differenthyaluronidase enzymes with distinct tissuedistributions and substrate specificities (26). Hyaluronidase deficiency has been de-scribed in only a single patient, a 14-year-oldgirl with nodular soft tissue periarticularmasses affecting the joints of her ankles, knees,and fingers. Other features included cutane-ous swelling, mild dysmorphic features, andshort stature, with normal joint mobility andintelligence. Histological examination dem-onstrated abnormal HA storage in lysosomesin macrophages and fibroblasts and an abnor-mally elevated serum HA concentration (27).

Diagnosis

Urine total mucopolysaccharide excretionis elevated.

Excretion of specific mucopolysaccharides,fractionated by thin-layer chromatography,electrophoresis, or isoelectric focusing, isabnormal (Table 43-1).

Deficient activity of specific lysosomal en-zyme confirms the diagnosis.

DNA testing is available by either gene se-quencing or targeted mutation analysis formost of the disorders.

Prenatal diagnosis is possible for the MPSsby enzyme assay on chorionic villus tissue orcultured amniocytes and by molecular stud-ies in families where the underlying defect is

known. Carrier testing, either by enzyme as-say or molecular studies, is also feasible.

Molecular testing is preferred for detectingcarriers of the X-linked Hunter syndromebecause of the influence of X-inactivationon iduronate sulfatase activity, which canlead to both false-positive and false-negativeresults.

Encouraging new studies demonstrate thefeasibility of identifying patients with thesedisorders presymptomatically by testingnewborn screening blood spots using a tan-dem mass spectrometrybased approach(28). This is particularly important because

treatment by enzyme replacement therapy(ERT) is most effective when initiated asearly as possible, ideally before the onset ofsymptoms (see below).

Treatment Supportive management for theMPSs includes ventriculoperitoneal shuntingfor communicating hydrocephalus, spinal fu-sion for cord compression, adenoidectomyand tonsillectomy, hernia repair, corneal trans-plants, and median nerve release for carpaltunnel syndrome. Bone-marrow transplanta-

tion (BMT) is a therapy aimed at replacing themissing enzyme through introduction of an al-

logenic graft and has been performed withvarying degrees of success on patients withMPS-I, -II, -III, -VI, and -VII. Improvementhas been noted for many of the somatic abnor-malities associated with the MPSs, includingorganomegaly, facial appearance, joint stiff-ness, and breathing difficulties (29). Skeletaland neurological outcomes are more variable,and in some cases, no effect of BMT on thesesystems is appreciated, especially for MPS-IIand -III. For MPS-I, it appears likely that chil-dren under the age of 2 without significantdevelopmental delay may benefit, whereaschildren with significant developmental delay

may not achieve continuing mental develop-ment. Furthermore, the risks associated withpoor engraftment and graft-versus-host diseasehave resulted in significant morbidity andmortality associated with this procedure.Complications of BMT specific to MPSs, suchas myocardial infarction and pneumonitis,have been noted. Enzyme-replacement therapy (ERT) isplaying an increasingly important role in thetreatment of the MPSs, although efficacy islimited because recombinant enzymes do not

MPS patients typically appear normal at birth.

All disorders are characterized by a progres-sive (developmentally regressive) course.

Mental retardation and severe visceral in-volvement are seen in Hunter and Hurlersyndromes.

Mental retardation and minimal visceral in-volvement are seen in Sanfilippo syndrome.

Visceral involvement and normal intelligenceare seen in MaroteauxLamy syndrome.

Severe skeletal abnormalities and normalintelligence are seen in Morquio syndrome.

TABLE 43-1 Glycosaminoglycans in Different MPSs

Typical Clinical Findings, Mucopolysaccharidosis Affected Organ Systems

I II III IV VI VII IX

Dermatan sulfate Skeletoninternal organs

Heparan sulfate n Mental retardation

Keratan sulfate Skeleton

Chondroitin sulfate ()

Adapted with permission from Zschocke J, Hoffmann GF. Pathological glycosaminoglycans in different MPSs. In: Vademecum Metabolicum: Manual of Metabolic Paediatrics, 2nd ed.

Stuttgart: Schattauer; 2004.

Urine screening for abnormal mucopolysac-charides is a useful first-line test through thedetermination of total glycosaminoglycan

concentration and the specific distribution ofindividual mucopolysaccharides.

Urine screening by measurement of totalmucopolysaccharides, without identificationof specific mucopolysaccharide species,may miss some patients who have normallevels but an abnormal distribution ofmucopolysaccharides.

Diagnosis is established by specific enzymeassays in leukocytes or cultured fibroblasts.

Carrier testing and prenatal diagnosis areavailable.


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Lysosomal Disorders

cross the bloodbrain barrier (30). Laronidase(Aldurazyme), or recombinantly produced -iduronidase, has been approved by the Foodand Drug Administration (FDA) as an ERTstrategy for MPS-I, following an initial evalua-tion in a randomized, placebo-controlled studyof 45 MPS-I patients. Promising early resultsshow improved pulmonary function and en-

durance in this small cohort of patients, al-though with no clear evidence of CNS im-provement (31). Specifically, ERT has beenshown efficacious only in those more mildlyaffected MPS-I patients without CNS involve-ment (i.e., MPS-IH/S and MPS-IS). More de-tailed long-term studies of outcomes followinglaronidase treatment are currently underway. Recently, ERT has also been approved forthe treatment of MPS-II and -VI, with newapproaches being evaluated for targeting di-rectly to the CNS in MPS-I and -II and poten-tially for MPS-III. The development of an ERTstrategy is also underway for MPS-IV (32,33).

DISORDERS OF LYSOSOMALENYZME LOCALIZATION

I-Cell Disease and Pseudo-HurlerPolydystrophy

Etiology/Pathophysiology I-cell disease (mu-colipidosis type II, or ML-II) and pseudo-Hurler polydystrophy (mucolipidosis type III,or ML-III) are autosomal recessive disorderscharacterized by deficient activity of multiplelysosomal enzymes, including those involved

in the catabolism of mucopolysaccharides,oligosaccharides, and sphingolipids (34). Theterm mucolipidosis reflects the constellationof clinical features shared by the mucopoly-saccharidoses and sphingolipidoses, includingorganomegaly, coarse facies, restricted jointmovement, and psychomotor retardation. The primary defect for both ML-II andML-III lies in the enzyme N-acetylglucos-aminyl-1-phosphotranseferase, which is re-quired for proper posttranslational processingof lysosomal acid hydrolases and their subse-quent import into lysosomes. During normallysosomal biogenesis, phosphotransferase

participates in the formation of a mannose-6-phosphate recognition marker on enzymesdestined for the lysosomes. Absence of thismarker leads to the inappropriate secretion ofnumerous lysosomal enzymes outside cellsand to their deficiency inside lysosomes,where they would normally function at anacidic pH (see Figure 43-10). This, in turn,leads to abnormal storage of lysosomal sub-strates, including mucopolysaccharides, oli-gosaccharides, and sphingolipids and ulti-mately to cell toxicity and death (6). Phosphotransferase itself is a multisub-united enzyme, with all reported cases of

ML-II and some cases of ML-III due to muta-tions in the -subunit gene. Other cases ofML-III have been shown to be genetically dis-tinct and due to mutations in the -subunitgene. Patients with ML-II are more severelyaffected, whereas ML-III appears to have alater onset and milder course. There is goodevidence for genotype/phenotype correlation,

with ML-III patients retaining some residualphosphotransferase activity. I-cell disease is so named because of charac-teristic inclusion bodies seen in the cytoplasmof fibroblasts and other cells of mesenchymalorigin. These inclusions represent membrane-bound vacuoles containing electron-lucent orfibrillogranular material and include muco-polysaccharides, oligosaccharides, and lipids.Multiple organs and tissues are affected, in-cluding the skeletal, central nervous, muscu-lar, and cardiac systems. In particular, thevacuolization of cells of the heart valves leadsto valvular thickening and subsequent cardiac

insufficiency. Patients with ML-III demon-strate intracellular inclusions similar to but notas prominent as those in ML-II.

Clinical Presentation Patients with I-cell diseasepresent with many features of Hurler syndrome(MPS-I) but are distinguished from Hurler pa-tients by earlier onset, more rapidly progressivecourse, prominent gingival hyperplasia, lack ofexcessive mucopolysacchariduria, and coarsefacies at birth. Other presenting symptoms

include decreased birth weight and length, hypotonia, and joint immobility. The skeletal system of ML-II patients is severely affected, withabnormalities including anterior beaking andwedging of vertebral bodies, kyphoscoliosisgibbus deformity, and widening of the ribsML-II patients may develop valvular disease associated with the presence of vacuolated fibro

blasts in heart valves (35). Tracheal narrowingalso can occur as a result of glycosaminoglycandeposition (36). Other abnormalities includepsychomotor retardation and organomegaly(including liver, spleen, and heart). Death typically occurs between 5 and 8 years of age frompneumonia or congestive heart failure. Patients with ML-III have a later onset osymptoms than those with ML-II, as well as amilder and more slowly progressive courseOnset is typically between 2 and 4 years o

Most I-cell patients do not have abnormalmucopolysaccharide excretion.

Diagnosis of either ML-II or ML-III is by dem-onstration of abnormally increased lysosomalenzyme activities in serum and decreasedactivities in cells.

The distinction between ML-II and ML-III ismade on clinical grounds, with ML-III patientspresenting later and showing a milder diseaseprogression.

Asn

PP

Lysosome

5

4

Asn Asn

PP

Asn

PP

UDP-

UMP

1

Golgi

2

3

Mannose-6-Phosphate receptor

Mannose

N-acetylglucosamine

6

Asn

FIGURE 43-10.Targeting of lysosomal enzymes via the mannose-6-phosphate receptor: 1) transfer of N-acetylglucosamine-1-

phosphate to mannose via phosphotransferase (defective in ML-II and ML-III), 2) removal of N-acetylglucosamine exposing the

mannose-6-phosphate marker, 3) recognition and binding of lysosomal enzymes to the mannose-6-phosphate receptor,

4) transport of lysosomal enzymes to lysosomes, 5) recycling of mannose-6-phosphate receptors back to the Golgi membrane,

6) abnormal secretion of lysosomal enzymes that fail to acquire the mannose-6-phosphate marker, as in ML-II and ML-III.


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age, with survival possible into adulthood.Features include growth retardation, stiffjoints, claw-hand deformity, mild coarseningof facial features, and mild psychomotor de-lay. In contrast to patients with ML-II, theskeletal dysplasia is slowly progressive overmany years. Neurological involvement isalso characteristically milder than in ML-II,with mental retardation reported in approxi-mately 50% of ML-III patients.

Diagnosis

Determination of lysosomal enzyme activ-ity in serum (not in fibroblasts or cells) is

useful in the diagnosis of I-cell disease be-cause these enzymes are secreted out ofthe cells.

Normal to mildly increased mucopolysac-chariduria may be present (Table 43-2).

Inclusion bodies (membrane-bound vacu-oles) are found in fibroblasts.

Assays for phosphotransferase activity arereliable but not widely available on aclinical basis.

Prenatal diagnosis is accomplished bydemonstration of increased lysosomal en-zyme activities (e.g., -hexosaminidase and

arylsulfatase A) in cell-free amniotic fluidand decreased intracellular activities incultured amniocytes.

Treatment There is no definitive treatmentfor either disorder. Supportive therapies in-clude antibiotic treatment of recurrent respi-ratory infections, physical therapy for jointlimitations, and hip-replacement surgery.BMT has been performed on a limited num-ber of patients with I-cell disease, with appar-ent prevention of cardiopulmonary compli-cations and continued neurocognitivedevelopment (37,38). Treatment of two ML-III patients with the bisphosphonate pami-dronate resulted in significant improvementin mobility and reduction in bone pain (39).

SPHINGOLIPIDOSES

Tay-Sachs Disease and SandhoffDisease: The GM2-Gangliosidoses

Etiology/Pathophysiology The GM2-gangliosi-doses are autosomal recessive conditions thatfeature abnormal accumulation of gangliosideGM2and other related glycolipids in neuronallysosomes secondary to deficiency of -hexosa-

minidase. There are two forms of -hexosa-minidase, Hex A (consisting of an and a subunit) and Hex B (consisting of two sub-units). Tay-Sachs disease is caused by muta-tions in the gene coding for the subunit of-hexosaminidase (Hex A deficiency).Sandhoff disease is caused by mutations inthe gene encoding the subunit of -hexosa-minidase (Hex A and Hex B deficiency) (seeFigure 43-11). Both conditions are panethnic,although Tay-Sachs disease has a higher preva-lence in the Ashkenazi Jewish population. Inaddition, GM2-activator deficiency (also some-times referred to as variant AB) results in a Tay-

Sachs-like phenotype. GM2 activator forms acomplex with gangliosides that is presented to-hexosaminidase in order for hydrolysis tooccur (40). The nervous system is the site of pa-thology in Tay-Sachs disease. Membranous cy-toplasmic bodies composed of GM2-ganglioside,cholesterol, and phospholipids are foundthroughout the central and peripheral nervoussystems. In Sandhoff disease, the nervous sys-tem pathology is similar to that seen in Tay-Sachs disease. However, additional storagematerial in Sandhoff disease is found in liver,spleen, lung, lymph nodes, and kidney.Nevertheless, such visceral storage usually

does not lead to significant organomegaly. Thepathogenesis of the GM2-gangliosidoses is notclearly understood. Altered neuronal cellmembrane ganglioside structure leading to ab-normal neuronal connections and the forma-tion of toxic compounds (e.g., lysogangliosideGM2) may contribute to disease progression.Lysosphingolipids have been shown to inhibitprotein kinase C and, in theory, may cause ab-errant neuronal signal transduction. Recent

experiments in mouse models have implicatedCNS inflammation in disease pathogenesis inboth GM2- and GM1-gangliosidoses (41).

Clinical Presentation The acute infantile formsof Tay-Sachs disease, Sandhoff disease, andGM2-activator deficiency present similarly withweakness, usually appearing at between 3 and5 months. Progressive loss of neurologicalfunction occurs insidiously at first. Hypotonia,poor head control, an exaggerated startle re-flex, seizures, and blindness supervene. Acherry-red spot is typical on ophthalmologicalevaluation. Macrocephaly secondary to cere-bral gliosis is noted from about age 18 months.Decerebrate posturing and eventual completeunresponsiveness occur in the second year.Death usually is caused by pneumonia and oc-curs at between 2 and 5 years of age. Later-onset forms of Tay-Sachs disease andSandhoff disease exist. Late-onset juvenileforms of GM2-gangliosidoses typically presentbetween the ages of 2 and 10 years with ataxia,dystonia, progressive spasticity, dementia, andincreasing seizures. Affected individuals usu-ally die in the second decade. Adult-onsetforms of disease are even more insidious inprogression. Patients may have normal intel-ligence, although other neurological prob-lems, including dystonia, ataxia, and spino-cerebellar degeneration, may occur.Psychiatric problems, including psychosis,are relatively common in late-onset formsTay-Sachs disease and Sandhoff disease.

Diagnosis

Urine oligosaccharide analysis may show an

increase in N-acetylglucosaminyl oligosac-charides in Sandhoff disease (Table 43-3)but is normal in Tay-Sachs disease becausesuch compounds are not stored in the latter.

Decreased -hexosaminidase A is present inplasma, leukocytes, fibroblasts, and tissuesin Tay-Sachs disease. A combined defi-ciency of-hexosaminidase A and -hexosa-minidase B is present in Sandhoff disease.Specific assays to detect GM2-activator

TABLE 43-2 Laboratory Findings: ML-II and ML-III

Decreased Increased

N-Acetylglucosamine-1-phosphotransferase activity Mucopolysacchariduria (normal to mildly elevated)

Serum -hexosaminidase (1020)

Serum arylsulfatase A (1020)

-Hexosaminidase isoenzymes

Hex A Hex B

FIGUR E 43-11.Molecular mechanisms of TaySachs and Sandhoff diseases.


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activity or the amount of GM2-activator pro-

tein are needed for a biochemical diagnosisof variant AB.

Mutation analysis is widely available forthe common Ashkenazi Jewish mutations.In this population, two mutations accountfor most cases of infantile onset Tay-Sachsdisease.

Healthy individuals have been identifiedwho have an apparent deficiency of Hex Aactivity when measured by standard tech-niques. These pseudodeficient individualshave been detected most often as part ofscreening programs.

Prenatal diagnosis is possible by measuring-hexosaminidase activity in amniocytes orchorionic villi. If the mutations are known,DNA analysis is also possible. It is espe-cially important to perform mutation anal-ysis for alleles known to cause pseudodefi-ciency if parental mutations are not knownso that a clinically unaffected fetus will notbe mistaken for classic disease.

Treatment Therapy is supportive. ERT byintravenous infusion has been attempted in afew patients, but because enzyme does notcross the bloodbrain barrier, this approach isineffective (42). Bone marrow transplantation

has been attempted, but with no clear success.Substrate-reduction therapy using N-butyl-deoxynorjirimycin (Miglustat) has shown suc-cess in a mouse model of Tay-Sachs disease,and clinical trials are under way in late-onsetforms of Tay-Sachs disease (43).

NiemannPick DiseaseTypes A and B

Etiology/Pathophysiology NiemannPickdisease (NPD) types A and B are autosomalrecessive conditions caused by acid sphingo-myelinase (ASM) deficiency, which leads to

abnormal accumulation of sphingomyelin inlysosomes and secondary increases in choles-terol and other lipids. The more severe type

A form is characterized by undetectable toless than 5% of normal ASM activity whenmeasured in leukocytes or fibroblasts, whereas

ASM activity in type B is usually higher, al-though some overlap exists. Sphingomyelin isa major component of the plasma membraneand membranes of subcellular organelles inmost cell types. NPD types A and B are pan-ethnic, but NPD type A has a relatively highprevalence in the Ashkenazi Jewish popula-

tion. The monocytemacrophage system isthe site of the greatest storage of sphingomy-elin. The stored material has a mulberry-likeor honeycomb-like appearance in histiocytes.Such cells are often referred to asfoam cellsorNiemannPick cells (see Figure 43-12).Similar-appearing cells may be found in GM1-gangliosidosis, Wolman disease, and choles-terol ester storage disease. In NPD type A, thespleen and lymph nodes may be completely

filled with foam cells, but all organ systemshave some degree of infiltration.Sphingomyelin and its downstream meta-bolic intermediates have important functionsin cellular signal transduction. For example,sphingosine is a potent inhibitor of proteinkinase C activity (the protein kinase C familyof serinethreonine kinases is involved inmultiple cell-signaling pathways). Ceramideis a lipid second messenger in diverse path-ways involving apoptosis, cell division and dif-ferentiation, and sterol homeostasis.Lysosphingolipids also accumulate in NPDand may contribute to cell dysfunction and

affect apoptosis. Therefore, NPD patientsmay have abnormalities in a variety of cell-signaling pathways that contribute to diseasepathophysiology, although the precise defectsremain to be elucidated. Massive accu-mulation of bis(monoacylglycero)phosphatealso occurs, but the role this plays in diseasepathogenesis is unclear.

Clinical Presentation NPD type A presentsin infancy, usually within the first fewmonths, with abdominal distension and hep-atosplenomegaly. Nonimmune hydrops feta-lis has been described (44). Feeding difficul-

ties, intermittent vomiting, and constipationare common. Developmental delay usually ipresent by 6 months, and regression occursNeurological features include hypotonia andweakness. In later stages, spasticity supervenes. Although about 50% of children wilhave a cherry red spot noted on ophthalmological examination, visual loss is rare. Lipid

deposits may cause corneal and retinal opacification. Pulmonary involvement consistingof alveolar infiltration also may occur but iusually not a significant problem, althoughepisodes of bronchitis and aspiration pneumonia may be severe. Growth is impairedand osteoporosis is common; such featureare likely secondary to poor nutrition andbone infiltration. These children usually succumb by age 3 years. Asphyxia or pneumonimay represent the terminal event. In contrast, NPD type B is a milder condition with a more variable clinical presentation and course. For example, some may have

significant organomegaly in infancy, whereaothers only develop signs in later adulthoodHowever, most are diagnosed during infancyor childhood when hepatosplenomegaly inoted on a routine examination. Still mildeforms are not detected until adulthood. Pulmonary involvement often develops, secondary to alveolar infiltration, and may be severeIn some cases, liver disease is severe and progresses to cirrhosis. Hyperlipidemia is common. Intelligence is normal. Interestinglysome patients with NPD type B have beennoted to have cherry red maculae. Survivais usually into adulthood, although death

may occur in childhood or adolescence. Significant liver involvement with cirrhosis, respiratory disease (e.g., pneumonia), and copulmonale may be life-threatening (45).

Diagnosis

Decreased acid sphingomyelinase activitis present in peripheral blood leukocytes ofibroblasts (Table 43-4).

Sometimes the diagnosis is made whenNiemannPick cells are detected after abone marrow biopsy is performed for suspected malignancy or a liver biopsy is undertaken to investigate hepatomegaly.

X-rays may show osteoporosis and pulmonary alveolar infiltration.

Decreased plasma high-density lipoprotein(HDL) cholesterol and increased triglycerides and low-density lipoprotein (LDLcholesterol may occur (46) .

Because three common alleles are responsible for over 90% of cases of NPD type Ain the Ashkenazi Jewish population, molecular diagnosis may be relatively straightforward in this group. In contrast, diverseprivate mutations typically are present in

TABLE 43-3 Laboratory Findings: TaySachs/Sandhoff Diseases

Decreased Increased

-Hexosaminidase activity Tissue ganglioside GM2content

UrineN-acetylglucosaminyl oligosaccharides (Sandhoff)

FIGURE 43-12.Bone marrow with focal aggregatesof multivacuolated histiocytes typical of NeimannPick

disease. This histiocyte morphology, however, is not

specific for this disease. (Courtesy of Daniel Arber, M.D.,Stanford University Pathology Department.)


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other ethnic groups, and only will be de-tected by DNA sequencing.

R608 is a neuroprotective (i.e., typeB) mutation in the Ashkenazi Jewishpopulation.

Prenatal diagnosis is possible by measuringASM activity in amniocytes or chorionicvilli. If the mutations are known, DNAanalysis is also possible.

Treatment In general, treatment is support-ive for all types of NPD. Liver transplantation

has had some success in severe nonneuro-pathic cases. Bone marrow transplantationhas been performed in both types A and B.No change in the neurological course wasnoted in type A disease. ERT may be of ben-efit in the later-onset form of NPD.Improvement of organomegaly followingbone marrow transplantation has been ob-served in NPD type B (47). A clinical trialusing ERT is scheduled to start soon for NPDtype B. Other treatments, including genetherapy, are currently under investigation.

NiemannPick Disease Type C

Etiology/Pathophysiology NPD type C is anautosomal recessive, panethnic conditioncaused by a defect in cellular cholesterol traf-ficking leading to late-endosomal/lysosomalstorage of unesterified cholesterol. The ma-jority (~90%) of affected individuals carrymutations in NPC1, a gene that encodes aprotein that localizes in late endosomes andinteracts with lysosomes in the trans-Golginetwork. The exact function of NPC1 pro-tein is unknown (48). A minority of patientscarry mutations in HE1, which codes for aprotein present in lysosomes and late endo-

somes that may play a role in the egress ofcholesterol and glycolipids from lysosomes(49). Variant forms also exist. NPD type C ischaracterized by the presence of foam cells orsea-blue histiocytes in visceral organs and theCNS (50). Neurofibrillary tangles are seen inthe CNS of patients who have a prolongedneurological course.

Clinical Presentation NPD type C is a pro-gressive neurodegenerative disease that haswide clinical variability. Vertical supranuclearophthalmoplegia (upward-gaze palsy), ataxia,dystonia, behavioral problems and dementia

are characteristic of the classical disease phe-notype. Hepatosplenomegaly is variable butcan be severe and represent the initial sign ofunderlying disease. Although most cases pres-ent in childhood, onset may vary from theneonatal period to adulthood. Severe, lethal

neonatal liver disease (neonatal hepatitis)and hydrops fetalis may occur. Psychiatricillness, including dementia, is a common fea-ture in adult variants. Most affected individu-als die after one to three decades of steadydeterioration.

Diagnosis

An abnormal pattern of fibroblast cholesterolis seen by Filipin fluorescence staining.

Abnormal cholesterol esterification is seenin cultured fibroblasts (Table 43-5).

Foam cells or sea-blue histiocytes are pres-

ent in many tissues. Polymorphous cytoplasmic bodies may be

seen on electron microscopy of skin orconjunctiva.

ASM activity may be normal, low, or evenelevated.

Variant forms exist in which biochemicalstudies are near normal. These forms canbe detected using a fluorescent sphingo-lipid analogue (BODIPY-lactosylceramide)when analyzing fibroblasts.

Mutation analysis is available.

Prenatal diagnosis is possible by measuring

ASM activity in amniocytes or chorionicvilli. If the mutations are known, DNAanalysis is also possible.

Treatment Definitive therapy is not avail-able, so care and management are support-ive. Substrate-reduction therapy withMiglustat, an inhibitor of glycosphingolipid

synthesis, has shown early encouraging re-sults in a NPD type C patient and is underinvestigation (51).

Gaucher Disease

Etiology/Pathophysiology Gaucher disease isthe most prevalent lysosomal disorder. A defi-

ciency of -glucocerebrosidase (-glucosi-dase) results in storage of the lipid glucosylce-ramide, an intermediate in the catabolism ofgloboside and gangliosides. Gaucher diseasecan be somewhat artificially divided into threeforms that can be differentiated by the relativedegree of neurological involvement. In real-ity, there is probably a continuous spectrum ofdisease phenotypes, but the old classificationis nevertheless useful. Although Gaucher dis-ease type 1 is panethnic, it occurs most fre-quently in the Ashkenazi Jewish population(~1:1000). All forms of Gaucher disease areinherited in an autosomal recessive fashion.

Lipid-laden cells (Gaucher cells) derivedfrom the monocytemacrophage system con-taining cytoplasm with a wrinkled tissue pa-per or crumpled silk appearance are char-acteristic. Liver, spleen, and brain (inneuronopathic forms) of affected individualshave shown markedly increased glucosylce-ramide content. In Gaucher disease type 1,Gaucher cells and glucosylceramide accumu-late in the vascular periadventitial areas of the

VirchowRobinow spaces. Gaucher cells areespecially prominent in spleen, liver sinusoids,hepatic Kupffer cells, and lymph nodes.Storage in the liver and spleen can lead to

massive hepatosplenomegaly. Fibrosis in sys-temic organs and brain gliosis occur.Progressive accumulation of Gaucher cells inbone marrow, vascular compromise, and in-farction lead to skeletal complications, includ-ing osteopenia, osteosclerosis, osteonecrosis(e.g., avascular necrosis of the femoral head),painful bone crises, and remodeling abnor-malities. Gaucher cells can coalesce to form apseudotumorous lesion (gaucheroma) thatmay resemble a chondrosarcoma. In neuro-pathic forms of Gaucher disease, significantamounts of glucosylceramide and glucosyl-sphingosine are present in the CNS.

Clinical Presentation Type 1 has a variablephenotype, ranging from asymptomatic indi-viduals to children who have massive hepato-splenomegaly, pancytopenia, and severeskeletal abnormalities (52). Common present-ing signs and symptoms include splenomegalywith associated hypersplenism, epistaxis, easy

TABLE 43-4 Laboratory Findings: NiemannPick Disease Types A and B

Decreased Increased

Acid sphingomyelinase activity Tissue sphingolipid and cholesterol content(5% type A;10% type B) Plasma LDL cholesterolHemoglobin/hematocrit Plasma triglyceridesPlatelets

The molecular defects in NPD type C are dif-ferent from the defect present in NPD typesA and B.

TABLE 43-5 Laboratory Findings: NiemannPick Disease Type C

Decreased Increased

Ability to synthesize cholesterol esters Intracellular unesterified cholesterol


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bruising, and hepatomegaly. Hypersplenismand bone marrow infiltration lead to pancy-topenia. Although massive hepatomegalymay occur, hepatic failure or cirrhosis is rare.Growth retardation is often present in chil-dren, but bone lesions usually occur laterthan visceral involvement. Painful bone cri-ses may occur, especially during childhood

or adolescence. In children, acute hip in-volvement sometimes may be mistaken forLeggCalvPerthe disease. Gaucher diseasetype 1 also has been misdiagnosed as lym-phoma, leukemia, bleeding disorders, andosteomyelitis. Lung infiltration by Gauchercells may happen in children, but this is arare finding. Pulmonary hypertension, por-tal hypertension, and renal involvement areencountered rarely. Cancer, especially he-matological malignancies, appears to beslightly more common in individuals whohave Gaucher disease than in the generalpopulation.

Gaucher disease type 2 is a severe, progres-sive disorder that presents in infancy or earlychildhood with massive hepatosplenomegaly,failure to thrive, and progressive neurologicaldysfunction with spasticity, cortical thumbs,and opisthotonus. Strabismus and oculomo-tor apraxia may be the first sign of disease.Fetal hydrops and a congenital ichthyosis-likerash also have been described (44). Gaucher disease type 3 is intermediate inseverity between types 1 and 2. Severe, early-onset massive organomegaly and slowly pro-gressive neurological dysfunction are typical.Some affected individuals do not have massive

organomegaly. This form is relatively commonin the Norrbottnian region of Sweden.

Diagnosis

Decreased -glucosidase activity is presentin peripheral blood leukocytes or fibro-blasts (Table 43-6).

Sometimes the diagnosis becomes evidentwhen Gaucher cells are detected after abone marrow biopsy is performed for sus-pected malignancy or a liver biopsy is un-dertaken to investigate hepatomegaly.

Skeletal x-rays may reveal the characteris-

tic Erlenmeyer flask deformity of thedistal femur in Gaucher disease type 1.

Because well-established genotypepheno-type correlations exist, mutation analysis is

often performed. For example, the 1226G(N370S) mutation is considered to be neu-roprotective because it has never been de-tected in patients with neuronopathic dis-ease. On the other hand, homozygosity forthe 1448C (L444P) mutation is associatedwith neuronopathic disease, althoughthere may be exceptions.

Prenatal diagnosis is possible by measuring-glucosidase activity in amniocytes orchorionic villi. If the mutations are known,DNA analysis is also possible.

Treatment ERT is the mainstay of treatmentfor type 1 disease (53). Therapy consists ofbimonthly intravenous infusion of human-glucosidase manufactured using recombi-nant DNA techniques. ERT improves ane-mia, thrombocytopenia, hepatosplenomeg-aly, and bone crises. Prolonged treatmentover 2 or 3 years may be required for any no-ticeable improvement in skeletal disease.

Severe skeletal manifestations can be pre-vented if ERT is begun before irreversiblebone damage has occurred. Because presenta-tion in childhood is indicative of moderate orsevere disease, all children should be consid-ered for ERT therapy, even those with isolatedsplenomegaly. ERT also should be considered in thosewho have type 3 disease because of the rela-tively slow progression of neurological diseasein these individuals. There is still debatewhether the enzyme may reach the brain. Al-though a few type 2 patients have receivedERT, such treatment has no effect on the

devastating neurodegenerative course in thissubtype and generally is not recommended. N-Butyldeoxynorjirimycin (Miglustat) de-creases the rate of synthesis of glucocerebro-side, a sphingolipid that is involved in thesynthesis of complex lipid formation in thepathway common to Gaucher, Fabry, Tay-Sachs, and Sandhoff diseases. Decreased syn-thesis of the stored compound (substrate-reduction therapy [SRT]) is an alternativetreatment that has been approved recently forGaucher disease type 1. Oral SRT with Mi-glustat improves hepatosplenomegaly andhematological parameters. Its effect on bone

complications and the brain are unclear. Al-though SRT is not likely to replace ERT, itmay prove to be a useful adjunctive therapy.Currently in the United States, Miglustat is

approved by the FDA for use only when ERTis not a therapeutic option. Bisphosphonates (e.g., palmidronate) inhibit bone resorption and may prove usefuin the management of advanced bone disease, especially when used in conjunctionwith ERT. Symptomatic treatment of complications, including analgesics for pain cri

ses, repair of fractures, and joint replacement, is, of course, still important. Howeverwith the advent of ERT, the current therapeutic goal is the a prioriprevention of suchcomplications. Although BMT has been performed in Gaucher disease type 1 patients inthe past, such therapy is no longer recommended because of the availability of ERTBMT also has been performed in type 2 andtype 3 patients but has not changed thecourse of neurological deterioration. Genetherapy has shown promise in vitro and inanimal models of Gaucher disease but is noyet ready for clinical application.

Fabry Disease

Etiology/Pathophysiology Fabry disease is anX-linked disorder of glycosphingolipid metabolism caused by defects in the lysosomaenzyme -galactosidase A. This enzymecleaves -galactosyl moieties from a variety osubstrates, predominately globotriaosylceramide [galactosyl(1S4)galactosyl(1S4glucosyl(1S1)ceramide]. Other substrateinclude galabiosylceramide and blood groupB substances. The enzyme is deficient in altissues of affected males and variably defi

cient in heterozygous females, with mosshowing intermediate levels of -galactosidase A activity. Fabry disease has been reported in numerous ethnic groups and occurat an estimated frequency of 1 in 40,000males. The incidence in females is unknown(54). Over 150 different mutations in the galactosidase A gene have been identifiedincluding deletions, point mutations, generearrangements, and splice-site defectsHemizygous males with partial residual enzyme activity have been described with lateonset and milder course. Disease progressionin females is variable and depends not only

on the specific mutation but also on the pattern of X inactivation. Abnormal storage of globotriaosylceramideoccurs in lysosomes of the vascular endothelium, as well as in perithelial and smoothmuscle cells of the heart and kidney. Lespronounced storage also occurs in connective tissue, cornea, and ganglion and perineural cells of the autonomic nervous systemThis is seen as tissue deposits of crystallineglycosphingolipids that show birefringenceor the characteristic Maltese cross appearance, under polarization microscopy.

TABLE 43-6 Laboratory Findings: Gaucher Disease

Decreased Increased

-Glucosidase activity Angiotensin-converting enzyme

Hemoglobin/hematocrit Total (nonprostatic) acid phosphatase

Platelets Chitotriosidase

Tissue glucocerbroside content


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The primary tissues affected in Fabry dis-ease are skin, kidney, nervous system, eye,and heart. Skin abnormalities are manifest asprogressive teleangeictasia and angiokera-toma resulting from vascular damage in cap-illaries of the dermal papillae. Similarly, vas-cular abnormalities of the kidney, resultingfrom glycosphingolipid storage in the glom-

erulus and distal tubules, lead to progressiverenal dysfunction and, without treatment,end-stage renal disease. Nervous system stor-age appears to be confined to the peripheraland central autonomic nerve cells , leading toparesthesias, extreme pain, hypohidrosis, andgastrointestinal symptoms. The CNS alsocan be involved in that strokes and brainwhite matter changes can occur. Glyco-sphingolipid deposits in the eye lead to awhorl-like dystrophic corneal pattern charac-teristic of Fabry disease. Damage resultingfrom deposition in myocardial cells and val-vular fibrocytes leads to cardiomegaly, ven-

tricular hypertrophy, valvular disease, andeventually, congestive heart failure.

Clinical Presentation Hemizygous maleswith no detectable -galactosidase A activitytypically present in childhood or adoles-cence with pain and paresthesis of the ex-tremities, angiokeratoma, hypohidrosis, andcorneal whorls. The episodic, painful crisesassociated with Fabry disease can be debili-tating and often are triggered by fever, exer-cise, fatigue, or other external stress.Unfortunately, these symptoms in childrentypically do not lead to a diagnosis of Fabry

disease but sometimes are ignored, misun-derstood, or misdiagnosed as erythromyalgiaor other conditions (55). Over time, increas-ing damage to the kidneys and heart leads toproteinuria, hypertension, lymphedema,and uremia, as well as angina, electrocardio-graphic (ECG) abnormalities, ventricularhypertrophy, valvular disease, and conges-tive heart failure. Increasing storage of gly-cosphingolipids in the brain can lead totransient ischemic attacks and strokes.Gastrointestinal manifestations include ab-dominal pain, constipation or diarrhea, dif-ficulty gaining weight, and vomiting. Prior

to the availability of treatment by di

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