Mucopolysaccharidoses Chapter 13

13.1 Clinical Features

and Laboratory Investigations The mucopolysaccharidoses (MPS) constitute a fami- ly of heritable disorders caused by the deficiency of specific lysosomal enzymes involved in the degrada- tion of mucopolysaccharides (glycosaminoglycans).

The mucopolysaccharidoses are classified into six groups, which are further subdivided on the basis of genetic, biochemical, and clinical findings (Table 13.1). These disorders share a number of characteris- tic clinical features, although there is considerable variability among the MPS types and within one type of MPS.

MPS type I, inherited as an autosomal recessive disease, can be divided into three subtypes: Hurler syndrome, Scheie syndrome, and Hurler–Scheie syn- drome. The clinical phenotype in Hurler–Scheie syn- drome is intermediate between the severe presenta- tion of Hurler syndrome and the mild presentation of Scheie syndrome.

Children with Hurler syndrome (MPS I H) appear normal at birth. They may be unusually large in in- fancy, but subsequent growth is retarded, finally re- sulting in dwarfism. During the first year of life men- tal retardation becomes evident, and after several years this is followed by progressive deterioration.

Most children with Hurler syndrome manage to walk, but develop only limited language skills. They have a characteristic appearance. Prominent features are relative macrocephaly, a prominent forehead, coarse facial features, hypertelorism, flat nasal bridge, prominent bushy eyebrows, thick and dry hair, hir- sutism, thick skin, enlarged tongue, hypertrophic gums, short and broad hands with stubby fingers, short and broad feet, exaggerated lumbar lordosis, thoracic kyphosis, and a protuberant abdomen, frequently with umbilical and inguinal hernias. On physical examination hepatosplenomegaly is found.

Patients experience increasing joint stiffness and lim- itation of joint mobility, which may begin in early in- fancy. The preferentially affected joints are shoulders, fingers, and wrists. Deformities become apparent with claw hands and flexion contractures of elbows and knees. Vision becomes impaired due to progres- sive corneal clouding. Glaucoma, optic atrophy, and pigmentary retinal degeneration can contribute to the loss of vision. The majority of children have some degree of hearing loss, usually caused by a combina- tion of conductive and sensorineural problems. Most patients have recurrent upper respiratory tract infec- tions, copious nasal discharge, and ear infections.

Valvular heart disease is common. Occasionally patients have progressive communicating hydro-

Mucopolysaccharidoses

Table 13.1. Classification of the mucopolysaccharidoses

Number Eponym Enzyme deficiency Urinary glycosaminoglycan

MPS I H Hurler a-L-Iduronidase DS, HS

MPS I S Scheie a-L-Iduronidase DS, HS

MPS I H/S Hurler–Scheie a-L-Iduronidase DS, HS

MPS II Hunter Iduronate sulfatase DS, HS

MPS III A Sanfilippo A Heparan N-sulfatase HS

MPS III B Sanfilippo B a-N-Acetylglucosaminidase HS

MPS III C Sanfilippo C acetyl-CoA: a-glucosaminide acyltransferase HS MPS III D Sanfilippo D N-Acetylglucosamine 6-sulfatase HS

MPS IV A Morquio A Galactose 6-sulfatase KS, C-6-S

MPS IV B Morquio B b-Galactosidase KS

MPS V No longer used – –

MPS VI Maroteaux–Lamy N-Acetylgalactosamine 4-sulfatase DS

MPS VII Sly b-Glucuronidase DS, HS, C-4-S, C-6-S

MPS VIII No longer used – –

DS, dermatan sulfate; HS, heparan sulfate; KS, keratan sulfate; C-4-S, chondroitin-4-sulfate; C-6-S, chondroitin-6-sulfate.

cephalus caused by dysfunction of arachnoid villi, and some patients have overt signs of increased in- tracranial pressure. Signs of spinal cord compression may occur but are infrequent.

Not all mentioned signs and symptoms are obliga- tory and there is considerable clinical variability.

However, progressive physical and neurological dete- rioration is the rule. Patients with Hurler syndrome rarely survive beyond the age of 16 years. Obstructive airway disease caused by deposition of mucopolysac- charides in soft tissue, respiratory infections, and car- diac disease are the usual causes of death.

Scheie syndrome (MPS I S) represents a mild vari- ant of Hurler syndrome. Intelligence is normal. Com- mon abnormalities are restricted mobility of joints, development of claw hands, hirsutism, variable deaf- ness, corneal clouding, and aortic valve disease.

Stature is normal. Glaucoma and pigmentary retinal degeneration may occur, which together with corneal opacities lead to impaired vision. Neurological prob- lems may occur in the form of carpal tunnel syn- drome and cervical cord compression by the thick- ened dura. Psychosis has been described in adults with Scheie syndrome. First abnormalities are usual- ly noted in the second half of the first decade of life, and the disease is slowly progressive.

Hurler–Scheie syndrome (MPS I H/S) represents a variant of intermediate severity with onset of clinical signs and symptoms between 3 and 8 years. Most pa- tients have normal or near-normal intelligence, but slowly progressive loss of mental capacities may occur. Coarsening of facial features, corneal clouding, joint stiffness, and valvular cardiac disease are fre- quent. Cervical spinal cord compression may occur.

Development of communicating hydrocephalus is rare. Psychosis may occur in adulthood. Most patients survive well into adulthood. Cardiac complications and upper airway obstruction are the most common causes of death.

MPS type II or Hunter syndrome is an X-linked disorder with two clinical phenotypes, a severe type (MPS II A) and a mild type (MPS II B). The mild type is rarer than the severe type. The most important dis- tinguishing feature is the presence or absence of men- tal deterioration. In the severe type progressive intel- lectual decline occurs, whereas intellectual perfor- mance remains normal or relatively normal in the mild type. The age at onset of the severe form is usu- ally between 1 and 4 years of age. Early abnormalities are coarse facial features, enlargement of the tongue, growth retardation, mental retardation, severe behav- ioral problems, joint stiffness, gibbus formation, and skeletal deformities. Head growth is abnormally rapid initially, but slows down after several years.

Retinal degeneration may occur, but there is no corneal clouding. Occasionally characteristic skin changes are found. They consist of pebbly, ivory-col-

ored patches over the lower angle of the scapulae and sometimes over the pectoralis area, in the neck and on the lateral sides of upper arms and thighs. Progres- sive neurological impairment dominates the course of the disease. By the age of 6 years, developmental skills begin to plateau and to regress. By the age of 10 years, 90% of the patients are bedridden. The neuro- logical deterioration may be worsened by progressive communicating hydrocephalus. This problem usually arises between 7 and 10 years. Spinal cord compres- sion may contribute to the neurological deterioration.

Upper and lower respiratory tract disease is common.

Tracheal stenosis may occur. Ear infections and pro- gressive hearing impairment occur in most patients.

There is a high incidence of hepatosplenomegaly and inguinal and umbilical hernias. Chronic and in- tractable diarrhea is a troublesome problem in many of the patients. Cardiac disease is present with valvu- lar dysfunction, myocardial thickening, cardiac fail- ure, pulmonary hypertension, coronary artery nar- rowing, and myocardial infarction. In end-stage dis- ease convulsions may occur. Respiratory problems in the form of infection or obstruction or cardiac prob- lems superimposed on a condition of emaciation are the usual causes of death. Death usually occurs between 8 and 15 years of age.

In the mild variant of Hunter syndrome, onset of disease is usually between 2 and 6 years. Coarse facial appearance is the commonest presenting feature. In- telligence is preserved and there are no behavioral problems. There are, however, obvious somatic prob- lems: hepatosplenomegaly, cardiac symptoms (pri- marily valvular in origin), upper and lower respirato- ry tract disease, tracheal stenosis, and inguinal and umbilical herniae. Diarrhea is less frequent than in severe Hunter syndrome. Hearing impairment is common. Subtle corneal opacities have been found.

Retinal degeneration is much less marked than in severe Hunter syndrome. The picture of chronic papilledema has been observed in about 60% of the patients, probably due to the deposition of glyco- saminoglycans within the sclerae. The occurrence of hydrocephalus is exceptional. Head growth is, how- ever, abnormally rapid with evident macrocephaly.

Cervical myelopathy may occur secondary to at- lantoaxial subluxation and dural thickening. Carpal tunnel syndrome is common. Death usually occurs in early adulthood, although survival into the fifth and sixth decade has been described. Death results pri- marily from cardiac problems, respiratory infections, and upper respiratory airway obstruction.

Female patients with MPS II are extremely rare and are explained by unbalanced expression of the mutant X chromosome.

Sanfilippo syndrome comprises four different diseases, MPS III A, B, C, and D, which are caused by different enzyme deficiencies. Clinically, however,

Chapter 13 Mucopolysaccharidoses 124

they are indistinguishable. Sanfilippo syndrome pre- sents with great inter- and intrafamilial heterogene- ity. The clinical characteristics of the disease are rela- tively mild somatic features and severe, progressive mental deficiency. Early psychomotor development is usually slightly or moderately delayed. Speech devel- opment, in particular, is often slow and poor. Intellec- tual deterioration is usually evident by school age.

Dementia occurs early and progresses rapidly in some patients, but is more gradual in others. Behav- ioral disturbances are often dramatic with extreme restlessness and hyperkinesia. Some patients are withdrawn and lose contact with their environment.

Aggression is often present in stressful situations.

Most of the children are too mentally disabled to attend school, but some are able to attend primary school. Speech deteriorates, becomes slurred, the patient begins to stutter and eventually loses speech altogether. Motor functions are less frequently and less severely affected, but in some patients the gait be- comes unstable with frequent falling. Facial changes are mild or absent in most of the patients. Skeletal in- volvement is minimal, with only mild dysostosis mul- tiplex, kyphosis, scoliosis, and usually normal stature for age. Joint stiffness and contractures are mild and rarely cause loss of function. Some patients are macrocephalic, but most older patients have a normal head circumference and may even be microcephalic.

Hepatomegaly is usual in younger patients, but is less frequent in older patients. Splenomegaly is rare.

Other features that can be found are inguinal and umbilical herniae, coarse hair, hirsutism, and sen- sorineural hearing loss. Neurological findings are in- consistent; they may include hypotonia, hypertonia, hyporeflexia, hyperreflexia, tetraparesis, and muscu- lar atrophy. Corneas are usually not clouded, but pig- mentary degeneration of the retina may occur. Some patients develop epilepsy. Many patients develop swallowing difficulties with time, necessitating tube feeding at later stages. Infections and unexplained diarrhea are frequent problems. Cachexia and aspira- tion pneumonia are common causes of death. Death usually occurs in the second or third decade.

Morquio syndrome is characterized by marked skeletal involvement and preserved intellectual ca- pacities. Two types can be distinguished, MPS IV A and MPS IV B, characterized by different enzyme de- ficiencies. Presenting features of Morquio syndrome are growth retardation with dwarfism, short neck and trunk, pigeon breast deformity, kyphosis, hyperlor- dosis, scoliosis, genua valga, valgus deformity of the elbow, and ulnar deviation and broadening of the wrist. The tone appears to be decreased due to liga- mentous laxity. Decreased joint mobility may occur in the large joints. The teeth are usually widely spaced and there are numerous minute pits in the abnormal- ly thin enamel, causing the surface of the teeth to be

rough and discolored. Facial features are usually coarse and the mouth wide. Corneal opacities may be present but are usually mild. Hepatomegaly, cardiac valvular abnormalities, and inguinal and umbilical hernias may occur. Intelligence is usually normal or just below normal. Neurological complaints are caused by compression of the medulla or spinal cord due to atlantoaxial subluxation and diffuse thicken- ing of the cervical dura. The signs of cervical myelo- pathy are usually slowly progressive, but occasionally acute tetraplegia occurs. Cardiac valvular disease and cervical myelopathy contribute to death, which usual- ly occurs in late childhood or early adulthood. Sur- vival into the fourth and the fifth decade has been described. As a rule, MPS IV B has a later onset and slower course than MPS IV A, but severe forms of MPS IV B and mild forms of MPS IV A have been described. A variant of MPS IV B has been described with progressive mental handicap.

Maroteaux–Lamy syndrome or MPS VI clinically resembles Hurler disease, but intelligence is pre- served. The disease usually presents in the third year of life and is characterized by growth retardation, coarse facial features similar to but milder than those seen in Hurler syndrome, corneal clouding, joint con- tractures, claw hand deformities, kyphosis, protru- sion of the sternum, hepatosplenomegaly, umbilical and inguinal hernias, and mild hirsutism. Nerve entrapment syndromes may occur, in particular carpal tunnel syndrome. Myelopathy secondary to thickening of the cervical dura occurs frequently with the insidious development of spastic tetraparesis.

Exceptional cases with mental retardation have been described. Cardiac valvular dysfunction resulting in cardiac failure is the most common cause of death. In the severe forms death usually occurs in the second or third decade, but patients with milder variants of the disease have a longer life expectancy.

Sly syndrome or MPS VII is also characterized by considerable clinical variation. In the severe neonatal form, hydrops fetalis and dysostosis multiplex are prominent early features; the course is rapidly fatal.

The other end of the clinical spectrum is formed by patients with very mild clinical symptomatology, with normal intelligence, normal height, absence of coarse facial features, and minimal skeletal abnormalities.

The classical form of the disease is characterized by

coarse facial features, hepatosplenomegaly, diastasis

recti, umbilical and inguinal herniae, thoracolumbar

gibbus, short stature, metatarsus adductus, and vari-

ably present corneal clouding. Respiratory infections

are frequent. Early psychomotor development is nor-

mal, but after 2 or 3 years of life retardation becomes

evident. Retardation is usually moderate, but severe

mental deficiency has also been reported. Epilepsy is

rare.

Radiographs show skeletal changes in all MPS variants, but the dysostosis multiplex varies in sever- ity. Typical findings are cortical sclerosis and thicken- ing of the skull, which may involve the base and the vault. The pituitary fossa is often elongated and J-shaped. Teeth are widely spaced. The head is often scaphocephalic and there is early closure of cranial sutures, in particular the sagittal and lambdoid sutures. Orbits are shallow. Basilar impression may occur. In MPS IV odontoid dysplasia is a universal finding with a tendency to atlantoaxial subluxation.

Various types of vertebral dysplasia are seen. Clavi- cles are short and stubby. There is anterior flaring of the ribs, hypoplasia of the inferior portion of the iliac bones, flared iliac wings, oblique acetabular margins, and a valgus deformity of the hips. Long bones are short and broad with metaphyseal and epiphyseal de- formities. Cortical margins are wavy and scalloped.

Metacarpals and phalanges are widened and short- ened.

The MPS variants were originally classified ac- cording to the types of glycosaminoglycans excreted in the urine in addition to consideration of clinical features. In MPS I and II dermatan sulfate and he- paran sulfate are excreted, but inheritance is autoso- mal recessive in MPS I and X-linked in MPS II. MPS III is associated with excretion of heparan sulfate.

MPS IV is characterized by excretion of keratan sul- fate, MPS VI by excretion of dermatan sulfate. MPS VII is associated with excretion of dermatan sulfate, heparan sulfate, and chondroitin sulfate.A problem in the diagnosis of MPS IV is that keratosulfaturia can be fairly easily missed. Special sensitive techniques are required for the detection of urinary keratan sul- fate excretion. An additional problem of diagnosis in MPS IV is that keratan sulfate excretion may be di- minished both early and late in the disease process.

Peripheral blood cells may also show changes re- lated to the specific type of MPS. Alder–Reilly granu- lation, a coarse reddish-violet granulation present in neutrophils in blood films stained with May–Grün- wald–Giemsa or Wright stain, is found in MPS VI and MPS VII. Vacuolated lymphocytes may be present in MPS IV B. Occasionally vacuolated lymphocytes with basophilic inclusions can be seen in any of the MPS variants. Metachromatic inclusions in lymphocytes are most prominent in MPS III. On the whole, how- ever, vacuolation of lymphocytes is not usually prominent in MPS. Bone marrow aspirates will reveal the presence of storage cells.

Definitive diagnosis of the MPS is established by enzyme assays. It is important to realize that not all MPS patients have glycosaminoglycan elevations in urine. Therefore, enzyme assays should be performed in all cases with strong clinical suspicion. Prenatal diagnosis is possible for all MPS variants with en- zyme assays on cultured amniotic fluid cells or chori-

onic villus cells. Prenatal diagnosis poses a problem in Hunter syndrome because of the X-linked mode of inheritance.When the cells obtained are derived from only a few cell clones which predominantly express the mutant X chromosome, very low enzyme activity may be detected in a carrier female fetus. Hence, sex determination is essential in prenatal diagnosis of Hunter syndrome. In families in which the molecular defect has been elucidated, DNA-based prenatal diag- nosis is an option.

13.2 Pathology

Mental deficiency is an important clinical character- istic of MPS I H, MPS II, MPS III, and MPS VII. Neu- ropathological findings in the syndromes causing mental deficiency are similar. In particular, neuronal storage is confined to the MPS variants with intellec- tual problems.

The skull is sometimes grossly thickened. The lep- tomeninges are thickened and opalescent. There is a marked increase in connective tissue elements and there are numerous mononuclear cells containing large cytoplasmic vacuoles. These cells stain positive for glycosaminoglycans. The blood vessels running over the surface of the brain are prominent and enveloped by the thickened leptomeninges, which extend deep into the brain parenchyma.

The weight of the brain is usually at the upper lim- it of normal or slightly increased. The external sur- face is normal or the gyri are slightly atrophic. At the cut surfaces increased perivascular spaces with in- creased volumes of connective tissue are evident.

Hydrocephalus is a common finding caused by im- paired circulation of CSF through the subarachnoid spaces or dysfunction of the arachnoid granulations.

Within the brain there are two main pathological features which may occur in MPS: increase in perivas- cular connective tissue, and neuronal storage.

The neuronal changes are ubiquitous but their ex- tent varies in different parts of the brain. Generally, the large nerve cells in the cerebral cortex and brain stem are the most severely affected. The cytoplasm of neurons is distended by an excessive amount of accu- mulated material, which stains positively with vari- ous Sudan dyes and PAS, corresponding to the pres- ence of gangliosides.Variable numbers of neurons are in various stages of degeneration and shrinkage. Loss of nerve cells is usually mild. Electron microscopic examination of neurons shows several types of inclu- sions. The most characteristic are the zebra bodies.

Zebra bodies are single membrane-bound vacuoles filled with stacked transverse lamellae, separated at intervals by larger clear spaces. In rare instances the lamellae have a concentric arrangement and look very similar to the membranous cytoplasmic bodies

Chapter 13 Mucopolysaccharidoses 126

seen in the gangliosidoses. Granular inclusions are less common than zebra bodies. Transitional forms between zebra bodies and bodies with granular mate- rial may occur. Inclusions resembling lipofuscin granules are infrequent. All inclusion bodies have acid phosphatase activity, indicating their lysosomal origin. In MPS the formation of meganeurites has been reported as well as the formation of ectopic secondary neurites. These are identical to those described in GM

and GM

gangliosidoses.

The cerebral white matter and basal ganglia are characterized by perivascular lacunation. Radially oriented, round to oval cystic white matter abnormal- ities are found at cut surfaces. On microscopic exam- ination, the adventitia of vessels is abnormally thick and consists of a delicate fibrous network with nu- merous large cells containing large clear inclusions caused by storage of glycosaminoglycans. On electron microscopy they appear empty except for a variable amount of granular dispersed material. A few lamel- lar lipid inclusions resembling the zebra bodies are also observed. Loss of myelin may occur around the cysts but is not conspicuous. On occasion, focal areas of demyelination have been described. Some oligo- dendrocytes contain abnormal, clear inclusions.

In visceral organs a variable degree of cellular vac- uolation is seen caused by glycosaminoglycan accu- mulation. Hepatocytes and Kupffer cells store gly- cosaminoglycans, in particular in MPS I, II, and III, in which hepatic fibrosis may occur. In addition to gly- cosaminoglycans, Kupffer cells may store ganglio- sides. Glycosaminoglycan storage is found in lymph nodes, spleen, kidney, and the heart. Cardiac valvular dysfunction is caused by the presence of large foamy cells and an increase of connective tissue. Fibroblasts in skin, cornea, and conjunctiva, endothelial cells of the vascular system, smooth muscle cells, skeletal muscle cells, macrophages, epithelial cells of distal and collecting tubules of the kidney, chondrocytes, osteoblasts, and periosteal cells of bone and cartilage show glycosaminoglycan storage. There are irregular- ities in enchondral ossification with variations in size and shape of the diaphyses of the long bones, pe- riosteal fibrosis, and various degrees of fibrosis and lipid storage in marrow tissue.

13.3 Chemical Pathology

Chemical analysis of the brain and leptomeninges reveals a highly increased concentration of gly- cosaminoglycans. The level of glycosaminoglycans is much higher in the meninges than in brain tissue, where the largest amounts of glycosaminoglycans are found in vascular and perivascular tissue. In MPS I and MPS II, it is mainly dermatan sulfate that is stored, whereas in MPS III it is mainly heparan sulfate.

In MPS I, MPS II, and MPS III, chemical studies demonstrate that in neuronal perikarya glycosamino- glycans and gangliosides are increased. Ganglioside storage involves the gangliosides GM

, GM

, and GD

. These substances together amount to 65% of the gan- gliosides stored in neurons. The ganglioside storage is comparable in magnitude to the amounts stored in the gangliosidoses.

13.4 Pathogenetic Considerations

Proteoglycans are complex molecules consisting of long sulfated polysaccharide chains with up to 100 sugar residues covalently linked to a protein core.

Glycosaminoglycans, formerly called mucopolysac- charides, are degradation products derived by proteo- lytic removal of the protein core of proteoglycans.

Many enzymes are necessary in the intralysosomal stepwise degradation of each of the glycosaminogly- cans dermatan sulfate, heparan sulfate, keratan sul- fate, and chondroitin sulfate. In deficiencies of the re- lated enzymes the undegraded or partially degraded glycosaminoglycans are stored in the lysosomes.

The respective enzyme deficiencies in the var- ious forms of MPS are listed in Table 13.1. a-

- Iduronidase, the enzyme that is deficient in MPS I, is encoded by the gene IDUA, located on chromosome 4p16.3. It hydrolyzes terminal a-

-iduronate residues from dermatan sulfate and heparan sulfate. Iduronate sulfatase, the enzyme that is deficient in MPS II, is en- coded by the gene IDS, located on chromosome Xq28.

It removes a sulfate group from

-iduronate present in dermatan sulfate and heparan sulfate. In a concerted action, the four enzymes related to MPS III accom- plish removal of the variably substituted a-linked glucosamine residues from heparan sulfate. Heparan N-sulfatase, the enzyme that is deficient in MPS III A, is encoded by the gene MPS3A, located on chromo- some 17q25.3. It removes sulfate groups linked to the amino group of glucosamine. The enzyme is impor- tant in the breakdown of heparan sulfate. The enzyme is also called sulfamate sulfohydrolase or sulfamidase.

a-N-Acetylglucosaminidase, the enzyme deficient in

MPS III B, is encoded by the gene NAGLU, located on

chromosome 17q21. It removes N-acetylglucosamine

residues in heparan sulfate. Acetyl-CoA:a-glu-

cosamide acetyltransferase, the enzyme that is defi-

cient in MPS III C, is encoded by the gene MPS3C,

located on chromosome 14. It catalyzes the acylation

of glucosamine amino groups that have become ex-

posed by the action of heparan N-sulfatase. After the

acylation of glucosamine amino groups, a-N-acetyl-

glucosaminidase removes the N-acetylglucosamine

group. N-acetyl-glucosamine 6-sulfatase is deficient

in MPS III D; the gene, GNS or G6S, is located on chro-

mosome 12q14. This enzyme desulfates 6-sulfated N-

acetylglucosamine residues of heparan sulfate and keratan sulfate. Since hexosaminidase A can bypass the block in the degradation of keratan sulfate, only the block in the degradation of heparan sulfate is im- portant. Galactose 6-sulfatase, the enzyme deficient in MPS IV A, is encoded by GALNS, located on chro- mosome 16q24.3. It cleaves sulfate from 6-sulfated galactose residues of keratan sulfate and 6-sulfated N- acetylgalactosamine residues of chondroitin 6-sul- fate. b-Galactosidase, the enzyme deficient in MPS IV B, is encoded by a gene GLB1 located on chromosome 3p21.33. It removes galactose residues of keratan sul- fate. N-acetylgalactosamine 4-sulfatase, also called arylsulfatase B, is deficient in MPS VI. It is encoded by the gene ARSB, located on chromosome 5q13–14. It hydrolyzes the sulfate groups in the 4-position of N- acetylgalactosamine residues in dermatan sulfate and chondroitin 4-sulfate. Urinary chondroitin 4-sulfate is not elevated in MPS VI, probably because the enzy- matic block is bypassed by the action of lysosomal hyaluronidase. b-Glucuronidase, the enzyme defi- cient in MPS VII, is encoded by the gene GUSB, locat- ed on chromosome 7q21.11. It removes b-glucuronate residues present in dermatan sulfate, heparan sulfate, and chondroitin sulfate.

The same enzyme deficiency underlies MPS IV B and GM

gangliosidosis. b-Galactosidase hydrolyzes terminal b-linked galactose residues found in GM

ganglioside, glycoproteins, and oligosaccharides, as well as keratan sulfate. Deficiency of enzyme activity toward all substrates causes GM

gangliosidosis. A mutation that predominantly impairs catalytic activ- ity towards keratan sulfate results in MPS IV B.

In the absence of specific enzymes, nondegraded or partially degraded glycosaminoglycans accumu- late in lysosomes and are partially excreted in urine.

Glycosaminoglycans normally constitute the “ground substance” of connective tissue. They are attached to protein in proteoglycans, the macromolecular forms in which they exist in connective tissue. In MPS main- ly bone and connective tissue are affected, causing the most characteristic clinical signs and symptoms:

growth retardation, dysostosis multiplex, coarse facial features, joint stiffness, corneal opacities, valvu- lar heart disease, and upper airway narrowing. In the CNS storage of glycosaminoglycans also occurs in connective tissue elements. Thickening of the lep- tomeninges may lead to hydrocephalus and to com- pression of the spinal cord in the cervical region, resulting in cervical myelopathy. Subluxation of the odontoid process can contribute to spinal cord com- pression. Storage in perineural tissue may lead to en- trapment neuropathy. Within the brain, glycosamino- glycans are stored in the tissue around vessels.

In addition to glycosaminoglycans, there is evi- dence of accumulation of gangliosides (GM

, GM

, and GD

) in the brain of MPS patients, especially in

MPS I, II, and III. Intralysosomal storage of ganglio- sides leads to the formation of zebra bodies and membranous cytoplasmic bodies, similar to those seen in GM

and GM

gangliosidoses. The question is what causes the storage of gangliosides. Apart from b-galactosidase, none of the enzymes involved in MPS plays a role in ganglioside breakdown. It has been demonstrated, however, that the activity of sev- eral additional lysosomal enzymes is reduced in the MPS, probably as a result of inhibition by the accumu- lating glycosaminoglycans, and this decreased en- zyme activity may lead to ganglioside storage. The accumulation of gangliosides is probably responsible for the formation of meganeurites and ectopic sec- ondary neurites, as these are also seen in GM

and GM

gangliosidoses. It is striking that the ganglioside storage is only found in MPS subtypes characterized by mental deficiency. These phenomena are most probably related.

There is a striking clinical variability within all MPS subtypes. An example is found in MPS I, in which Hurler syndrome is the most severe variant, Scheie syndrome the mild variant, and the Hurler- Scheie syndrome in between. The Scheie syndrome was previously classified as a separate disease entity, MPS V, until it became known that deficiency of the same enzyme underlies both Hurler syndrome and Scheie syndrome. It is probable that the clinical heterogeneity is caused by the presence of different mutant alleles, the Hurler patients having two severe mutations and the Scheie patients two mild muta- tions. It is likely that the type of mutation determines the residual activities of the mutant enzymes, which are associated with wide clinical variation within as well as between clinical subgroups. Environmental factors and modifying genes may also play a role in clinical severity, being in particular responsible for intrafamilial variability. A special phenomenon is the rare occurrence of clinical disease in female MPS II carriers, caused by unbalanced inactivation of the normal X chromosome.

13.5 Therapy

Hematopoietic stem cell transplantation presently represents the best therapeutic option in most MPS variants, if performed early in the course of the dis- ease. In MPS I H, early transplantation with success- ful engraftment can preserve intellectual function and prevent or improve the systemic manifestations of the disease. Depending on the stage in which the transplantation is performed, mental decline is pre- vented or arrest or slowing of the mental regression is achieved. Progressive hydrocephalus requiring shunt- ing does not occur after transplantation. Hepato- splenomegaly, joint stiffness, upper airway obstruc-

Chapter 13 Mucopolysaccharidoses 128

tion, and cardiac problems resolve or improve. How- ever, hematopoietic stem cell transplantation does not reverse the progression of the skeletal abnormal- ities in MPS I H. Hematopoietic stem cell transplanta- tion also leads to improvement in MPS I H/S and MPS I S, but these patients may be better candidates for en- zyme replacement therapy. Hematopoietic stem cell transplantation in MPS II A and B may lead to im- provements with respect to organomegaly, airway obstruction, and cardiac function. However, cognitive decline occurs despite early successful transplanta- tion in MPS II A. In MPS II B cognitive function re- mains intact, as expected on the basis of the natural history of the disorder. As in MPS II, hematopoietic stem cell transplantation is able to effectively treat the somatic aspects of MPS III, but the progressive neu- rocognitive and behavioral deterioration that causes the dominant problems in the clinical picture of MPS III is not halted. For this reason, hematopoietic stem cell transplantation is generally not recommended for MPS III. Hematopoietic stem cell transplantation is unable to ameliorate the severe skeletal abnormali- ties which dominate the clinical phenotype in MPS IV, and this treatment is therefore not recommended for MPS IV. In MPS VI, hematopoietic stem cell trans- plantation leads to resolution of hepatosplenomegaly and airway obstruction, prevents further cardiopul- monary deterioration, and improves joint mobility.

The skeletal abnormalities, however, do not benefit from the treatment. The experience in MPS VII is lim- ited due to the rarity of the disease, but there is evi- dence for beneficial effects on neurocognitive, motor, and pulmonary outcome.

Enzyme replacement therapy has been applied so far only in MPS I. Administration of recombinant a-

-iduronidase leads to a decrease of the hepato- splenomegaly, increased growth rate in prepubertal patients, improved joint mobility, and decreased air- way obstruction. This mode of treatment is consid- ered for other MPS variants as well. Although sys- temic improvement is likely, no beneficial effects on the neurological manifestations is expected.

Various forms of in vivo and ex vivo gene therapy are being studied in animal models.

Symptomatic treatment is very important in MPS.

Corneal transplantation can be performed in cases of corneal clouding; however, poor vision caused by reti- nal degeneration or optic atrophy cannot be reversed.

Hearing aids may be helpful in cases of significant hearing loss. Exercise to optimize joint mobility should be started early. Airway obstruction may be alleviated by tonsillectomy, adenoidectomy, and, if necessary, tracheobronchial stent insertion. Some- times a tracheostomy is required. Cardiac evaluation at regular intervals with echocardiography is impor- tant. Cardiac valve replacement is occasionally per- formed in cases of valvular disease. Bacterial endo-

carditis prophylaxis should be advised for MPS pa- tients with valvular abnormalities. Progressive hydro- cephalus may require ventriculoperitoneal shunting.

Carpal tunnel syndrome is a common complication in MPS patients and surgical decompression should be performed early, before permanent nerve damage occurs. Cervical fusion to prevent atlantoaxial sub- luxation is performed to prevent or treat cervical spinal cord compression, especially in MPS IV. Anes- thesia poses a particular problem in MPS. Atlantoax- ial instability requires careful positioning and avoid- ance of hyperextension of the neck. Another problem may be difficulty in maintaining an adequate airway during anesthesia and postoperative airway obstruc- tion. Sudden cardiovascular collapse may be caused by a combination of valvular disease, myocardial thickening, systemic and pulmonary hypertension, and narrowing of coronary arteries, all contributing to congestive heart failure.

13.6 Magnetic Resonance Imaging

The MRI abnormalities found in MPS vary greatly in severity from absent or negligible to severe, with a marked variation among sibs. However, in them- selves, the abnormalities are fairly homogeneous.

Over the years many patients develop white matter abnormalities. These consist of multiple small spot- like lesions dispersed in the white matter, with a predilection for the parietal and occipital white mat- ter. The signal intensity follows the signal intensity of CSF, indicative of the cystic nature of the lesions. The cystic areas often have a radial orientation from the subependymal region toward the cortex (Figs. 13.1 and 13.2). Punched-out cystic areas are often also pre- sent in the corpus callosum, best visualized on the sagittal images (Figs. 13.1 and 13.2). These cystic white matter lesions represent the perivascular lacu- nae seen on histopathological examination. In excep- tional cases, the thalamus and basal ganglia have a honeycomb-like appearance, related to highly en- larged perivascular spaces in these areas. In addition, T

-weighted and FLAIR images may show multifocal smaller and larger hyperintense areas, the signal in- tensity of which does not follow that of CSF. These areas may become extensive and confluent, and prob- ably reflect gliosis, which is also seen on histopatho- logical examination. The white matter abnormalities can be progressive on follow-up MRI. MRI and CT have demonstrated that white matter abnormalities may occur in all MPS variants. MRI may show a delay in myelination in young children.

Another frequent observation consists of ventricu-

lar enlargement, with or without accompanying en-

largement of subarachnoid spaces. Enlargement of

CSF spaces may occur in all MPS variants. The ven-

tricular enlargement is of variable severity and is in some cases progressive. Some of the patients appear to have enlarged CSF spaces on the basis of diffuse atrophy of the brain parenchyma. In many cases, how- ever, the enlargement of the CSF spaces is caused by hydrocephalus as a consequence of disturbed CSF re- sorption. Signs of hydrocephalus are upward bulging

Chapter 13 Mucopolysaccharidoses 130

Fig. 13.1. A 3-year-old boy with Hurler syndrome (MPS I).

The sagittal T1-weighted images show the radial stripes of enlarged perivascular spaces, most prominent in the parietal region and also seen in the corpus callosum. The T2-weighted

images confirm the enlarged perivascular spaces and show more extensive areas of signal abnormality in the region of the perivascular spaces. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto

Fig. 13.2. A 4-year-old boy with Hunter syndrome (MPS II).The sagittal and axial T1-weighted images show the radial stripes of enlarged perivascular spaces, most prominent in the pari- etal region and the corpus callosum. The T2-weighted images confirm the enlarged perivascular spaces and show more ex- tensive signal abnormalities in the region of the perivascular spaces. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto

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Fig. 13.2.

Chapter 13 Mucopolysaccharidoses 132

Fig. 13.3. Spinal MRI of a 5-year-old boy with Maroteaux–

Lamy syndrome (MPS VI) shows abnormalities of the cranio- cervical junction, with deposits of mucopolysaccharide mate- rial around the dens, narrowing the spinal canal. The T2- weighted images show no free CSF space around the cervical

spinal cord. The cervical vertebrae show platyspondyly. In the lower part of the vertebral column, T12, L1, L2, and L3 are dys- morphic with agenesis of the anterior parts of the vertebrae, resulting in local kyphosis

Fig. 13.4. A 5-year-old boy with Morquio syndrome (MPS IV). The mid- sagittal images show the intradural mucopolysaccharide deposits, leading to severe narrowing of the arachnoid space at the level of the craniocervical junction with compression of the spinal cord. Courtesy of Dr. P. Tortori Donati, Department of Pediatric Neuroradiology, G. Gaslini Children’s Hospital, Genoa, Italy