Archives of Disease in Childhood 1995; 72: 263-267

PERSONAL PRACTICE

The mucopolysaccharidoses: a clinical review andguide to management

J E Wraith

The mucopolysaccharidoses are a group ofinherited metabolic disorders caused by a defi-ciency of specific lysosomal enzymes. Theenzyme deficiency results in interference withcellular function because of excess accumula-tion within the cells of partially degradedglycosaminoglycans (GAGS), which are alsoexcreted to excess in the urine of affectedpatients.

Although the mucopolysaccharidoses werefirst described clinically by Hunter in 1917,their biochemical basis was not fully elucidateduntil the 1950s and 1960s. More recently themolecular biology of many of the subtypes hasbeen described.1The ubiquitous nature of GAGS within the

connective tissue of the body results in a widerange of clinical effects. The type of GAGstored depends on the specific enzyme defi-ciency and classification of the disorders is nowbased upon these deficiencies, rather thanclinical features. The table outlines present dayclassification with details of the accumulatingcompounds and enzyme deficiencies, as well asthe eponym used for each condition. Excellentaccounts of the biochemical basis of themucopolysaccharidoses are available and thisarea will not be considered further.

In keeping with many other multisystemdisorders affected patients are often under the

Willink Biochemical care ofmany different clinicians and coordina-Genetics Unit, Royal tion of care can be difficult. A special clinic forManchester Children'sHospital, Pendlebury, children with mucopolysacchardoses has beenManchester M27 4HA established in the Willink Biochemical

Genetics Unit and this review outlines import-Correspondence to:Dr Wraith. ant management issues that occur with each

Classification of mucopolysaccharidoses and patients attending clinic

Stored No ofType Eponym material* Enzyme deficiency patients

MPS IH Hurler DS, HS IduronidaseMPS IS Scheie DS, HS Iduronidase 57MPS I H/S Hurler-Scheie DS, HS Iduronidase

compoundMPS II Hunter DS, HS Iduronate sulphate sulphatase 46MPS III A Sanfilippo HS Heparan-N-sulphatase 62MPS III B HS N-acetylglucosaminidase 13MPS III C HS Acetyl-CoA-glucosaminidase 4

acetyltransferaseMPS III D HS N-acetylglucosamine-6-sulphatase 0MPS IV A Morquio KS Galactosamine-6-sulphatase 38MPS IV B KS P-Galactosidase 0MPS VI Maroteaux-Lamy DS N-acetylgalactosamine-4-sulphatase 5MPS VII Sly CS, DS, HS 13-Glucuronidase 0

Total 225

*DS=dermatan sulphate, HS=heparan sulphate, KS=keratan sulphate, CH=chondroitinsulphate.

particular subtype. The information is basedon the clinical details of 225 patients who haveattended this clinic from the UK and abroad. Abreakdown of the patients has been appendedto the table.

General considerationsA multidisciplinary approach to managementis necessary. Paediatric subspecialties, such ascardiology, anaesthesia, orthopaedics, otor-hinolaryngology, ophthalmology, and neuro-surgery, as well as many paramedical groups:for example physiotherapy, occupationaltherapy, audiology, speech therapy and psy-chology, will all have an important input.Diagnosis and evaluation is best undertaken ina major centre. The creation of our specialclinic has allowed colleagues in the aboverelated specialties to become highly experi-enced in the management of complicationsassociated with the mucopolysaccharidoses.After assessment and counselling the subse-quent care of the children can often be sharedwith the local paediatrician.

Regular assessmentsAs with many chronic progressive disorders thechild has to be seen frequently enough to allowrecognition of potential problems, leaving theparents free to enjoy the periods of betterhealth. An annual assessment at the muco-polysaccharidoses clinic has proved valuable.Enough time is set aside to allow parents toexpress concerns and anxieties often notexpressed in subspecialty clinics. Often a shortstay in hospital can incorporate reviews by anumber of subspecialists and in this way theprogress of the disease can be monitored andcomplications recognised and treated early.

AnaesthesiaA number of reviews have highlighted thedifficulties associated with this group ofdisorders.24 A careful preoperative and peri-operative management plan is required ifdisaster is to be averted. Intubation is oftenextremely difficult, although this has beenhelped by the use of fibreoptic laryngoscopyand bronchoscopy. In difficult cases thelaryngeal mask airway has proved to be auseful additional aid. Anaesthesia must be

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undertaken only by anaesthetists expert inmaintaining paediatric airways and in centreswith adequate intensive care facilities. In theseverely affected patient operations shouldonly be performed for life threatening compli-cations or in an effort to greatly improve thechild's quality of life. Minor or cosmetic proce-dures should not be undertaken or should beperformed under local anaesthesia.

Eponyms, heterogeneity, and phenotypeThe mucopolysaccharidoses are most com-monly known by their eponomous titles, asoutlined in the table. However, as our under-standing has increased it has become increas-ingly clear that these are a gross simplification.Most commonly the disorders are divided into'mild' and 'severe' variants. For example, inMPS I the severe variant is known as Hurler'ssyndrome and the mild variant Scheie's syn-drome. Anything apparently not conforming tothis division is called Hurler/Scheie syndromeby most paediatricians. It is now apparent, likemost genetic disorders, that there is a continu-ous spectrum of phenotype from the verysevere to the most mildly affected. Genotypeanalysis, where known, in this group of dis-orders has confirmed that many differentmutations are responsible for these phenotypicdifferences. It is preferable now to speak interms of enzyme deficiency rather thaneponym, but as the latter are so well estab-lished it will take time for this to achieveuniversal acceptance.

Presenting featuresPatients with a mucopolysaccharidosis usuallypresent in one of three ways: (i) as a dysmor-phic syndrome, for example MPS I, MPS II,MPS VII; (ii) with severe behavioural distur-

Figure 1 Typicalfacialfeatures of Hurler's syndrome.

bance and dementia, for example MPS III; and(iii) with evidence of a severe bone dysplasia,moderate dysmorphism, and normal intelli-gence, for example MPS IV, MPS VI.

Particular problems associated with eachenzyme deficiencyMUCOPOLYSACCHARIDOSIS TYPE I,IDURONIDASE DEFICIENCY (MPS IH, MPS IS,MPS IH/S, HURLER'S SYNDROME, SCHEIE'SSYNDROME AND OTHER VARIANTS)Fifty seven patients with iduronidase defi-ciency have been assessed in the unit and thefull clinical spectrum ranging from death inearly infancy due to cardiomyopathy to nearnormal adult patients has been observed. Thecommonest phenotype is that of 'classical'Hurler's syndrome and a number of thesepatients have been found to be homozygous fora recently described common mutation in theiduronidase gene.5 The characteristic dysmor-phism associated with this disorder is familiarto all paediatricians (fig 1).

In the severely affected patient the clinicalcourse is dominated by airway problems andfrequent upper and lower respiratory infectionsare common. Diagnosis should be followed byimmediate referral to the ear, nose, and throatclinic as all affected children require treatmentfor upper airways obstruction and middle eardisease. Obstructive sleep apnoea is an almostuniversal finding. Initially this can be helped bytonsillectomy and adenoidectomy, but manypatients require nocturnal oxygen treatmentlater in the course of the illness.

Cardiac disease is very common and presen-tation and early death from cardiomyopathy isa recognised complication of this disease.6 Inother patients asymmetrical ventricular septalhypertrophy is a frequent finding early in thedisorder and is often followed by variablethickening of the mitral and aortic valves.Coronary insufficiency is known to occur andsudden death from arrythmia has beenassumed in some patients.

Despite these potentially severe physicalproblems early intellectual development isusually normal and affected patients do nothave severe learning difficulties until much laterin the course of the disease. The majority ofchildren attain some social skills and many arecapable of starting normal nursery schools.Mobility may be limited by joint stiffness whichis progressive, but usually not painful, and bythe protuberant abdomen due to hepato-splenomegaly. The latter is also probablyresponsible for the high incidence of umbilicaland inguinal hernias seen in these patients.

Hydrocephalus requiring shunt insertionwas noted in six patients. If ignored the headcan reach enormous proportions and makenursing of the child difficult in the latter stagesof the illness.

Corneal clouding can be very variable.Glaucoma is often quoted as a complication ofMPS I, but was seen in only one patient in thisseries. Sudden blindness occurred in onepatient with no apparent cause, electroretino-grams were normal, but visual evoked

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The mucopolysaccharidoses: a clinical review and guide to management

Figure 2A Radiograph of the lumbar-sacral spine in a patient with MPS IS showing thetypical lumbar-sacral spondylolisthesis. (B) Magnetic resonance image of the same patientshowing narrowing and compression of the spinal canal at the level of the spondylolisthesis.

responses absent. Magnetic resonance imagingof the visual pathways was normal.Death usually occurs in the first decade of

life and is most often due to cardiorespiratoryfailure.

In the adult patient with iduronidase defi-ciency, the dysmorphic features are often verymild and there are different priorities withregard to management. The clinical picture isusually dominated by the orthopaedic compli-cations of the disease. Poor hand function,partly due to chronic carpal tunnel syndrome isextremely common.7 Progressive joint stiffnessand severe back pain are usual. Radiography ofthe lower lumbar spine has shown a very highincidence of spondylolisthesis in these patientsand in some this has been associated withspinal cord compression (fig 1A and 2B). Asthe patient gets older corneal clouding mayinterfere with vision and corneal grafting hasbeen performed on two patients. In thesecircumstances it is essential to confirm that theloss of vision is not due to retinal disease.

In older patients mitral and/or aorticincompetence are common.The oldest patient seen in the clinic is

currently 48 years of age: she shares the samegenetic mutations as Scheie's original patient.8

MUCOPOLYSACCHARIDOSIS TYPE II, IDURONATESULPHATE SULPHATASE DEFICIENCY (MPSTYPE II, HUNTER'S SYNDROME)Forty six patients with this variant have beenreviewed. The vast majority of patients havebeen severely affected (35), but again a spec-trum of clinical effect can be observed.Severely affected patients share many of thefeatures of classic Hurler's syndrome, but tendto be milder and have less severe skeletalinvolvement. The classic nodular rash said tobe pathognomic of this disorder is rare and hasbeen observed in only two patients. Once again

ear, nose, and throat and airway problemsdominate the clinical course. In addition mostpatients are prone to severe bouts of diarrhoea,the cause of which remains obscure. In addi-tion we have observed other unusual manifes-tations of gastrointestinal dysfunction notpreviously appreciated, such as, spontaneousperforation of the stomach and intestinalpseudo-obstruction.

Progressive neurodegeneration results in avegetative existence for most patients fromearly teenage years with death around the ageof 15-16 years.

In mildly affected patients cervical myelo-pathy due to dural hyperplasia and thickeningof the ligamentum flavum is probablyinevitable. In patients with declining exercisetolerance or upper motor neurone signs in thelimbs, magnetic resonance imaging of thecraniocervical junction should be performed.At the same time the airway can be imaged andan assessment made of the inevitable anaes-thetic problems in this group. No operativeprocedure should be performed on a mildlyaffected MPS II patient until it has been estab-lished whether or not cervical cord compres-sion is present. The manipulation involved in adifficult anaesthetic can lead to sudden cordcompromise and result in quadriplegia.

It is interesting to note that even in mildlyaffected patients with normal intellect thatimaging of the central nervous system is oftengrossly abnormal (fig 3).The genetics of this mucopolysaccharidosis

differ from the others as the disorder is inher-ited as an X linked recessive. Only a minorityof affected boys have a demonstrable deletionin their iduronate sulphatase gene (20%), the

Figure 3 Computed tomogram ofan intellectually normalman aged 24 years with MPS II. Note the ventriculardilatation and 'cyst-like structures' in the cerebral matter.

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majority of defects being various point muta-tions.9

MUCOPOLYSACCHARIDOSIS TYPE III (MPS IIA,IIIB, mC, HID, SANFIUPPO'S SYNDROME)In this disorder four enzyme defects are knownto cause an identical clinical phenotype. This isthe commonest of the mucopolysaccharidosesin the UK and its management has beenreviewed recently.'0 Seventy nine patients withMPS III have been assessed. Again, hetero-geneity produces a variable clinical phenotypeand a spectrum of effect is noted. Somepatients are very mildly affected and it may bethat this disorder is underdiagnosed. Milddysmorphic features are combined with avery severe behavioural disturbance and thedisorder is extremely difficult to manage.The molecular basis of the commonest

variant ofMPS III is yet to be established.

MUCOPOLYSACCHARIDOSIS TYPE IV (MPS IVA,MPS IVB, MORQUIO'S SYNDROME)No patients with MPS IVB have been seen inthe unit; this appears to be a rare variant in theUK. Thirty eight patients with MPS IVA havebeen seen and assessed. Affected patients areof normal intelligence and the clinical pictureis dominated by a severe bone dysplasia.Skeletal radiographs are often abnormal frombirth, but diagnosis is usually established in thefirst year of life after parents notice the obviousspinal deformity associated with this disease.Motor milestones are achieved at the normal

times, but the gait becomes increasinglyabnormal due to the development of severegenu valgum secondary to ligamentous laxity;this, combined with the increasing sternal pro-trusion and severe pes planus, leads to a verycharacteristic posture. In the severe form ofthedisease height prognosis is extremely poor andfew patients will be taller than 100 cm asadults.The major complication of this mucopoly-

saccharidosis is the development of neurologicalabnormality secondary to cervical myelopathy(also occurs in MPS I but is less common).This may be of sudden onset resulting in deathafter a simple fall as has occurred in two ofour patients and a number of their siblings, notseen in the unit, or it may occur insidiouslywith a lack of exercise tolerance predating frankneurological abnormality. This complicationmust be looked for with vigour and we currentlyperform magnetic resonance imaging of thecraniocervical junction on an annual basis inpatients with MPS IV. It is our practice toperform prophylactic occipitocervical fusionin patients with instability. We do not waitfor the onset of neurological abnormality. Theinstability is due to a combination of a hypo-plastic, poorly ossified dens and ligamentouslaxity in the cervical spine. What has becomeclear is that successful fusion in the uppercervical region is often followed by progressiveinstability further down the cervical spine andmultiple fusions may be required in somepatients. This complication is most commonly

seen in patients who remain independentlymobile after the procedure. In patients who arechair bound before surgery, sitting posture maylead to subluxation ofvertebrae lower down thespinal column, for example in the mid-thoracicregion.

Affected patients are not dysmorphic, butdo have an increased incidence of ear, nose,and throat disease and in addition have char-acteristic teeth which are prone to dentalcaries. Fine corneal opacity is usual, but neveras severe as patients with MPS I. Aorticincompetence is a usual finding in the adultpatient. Life expectancy should be good ifcervical complications are avoided. Somepatients, however, develop progressive cardio-respiratory disease secondary to theirrestricted chest movement.

Again, there is a very wide spectrum ofclinical phenotype which has been broadlydivided into severe, intermediate, and mildMPS IV. The mildly affected patient can be ofnormal adult height and in our patients hipstiffness and pain appears to be the commonestmode of presentation.As adults patients with MPS IV often

develop aches and pains in various joints. Weassume that this is 'wear and tear' acceleratedby the abnormal joint posture. The symptomsrespond variably to analgesia and non-steroidalanti-inflammatory agents.

It has been proposed that the prognosis forgirls with this disorder is better than for boysand this was attributed to their 'less activelifestyle'."I In our patients we can detect nodifference in the severity of the disease betweenthe sexes and the incidence of cervical cordproblems is the same in both groups.

MUCOPOLYSACCHARIDOSIS TYPE VI,N-ACETYLGALACTOSAMINE-4-SULPHATASEDEFICIENCY (MPS VI, MAROTEAUX-LAMYSYNDROME)This mucopolysaccharidosis appears to be veryrare in the UK. Only five patients haveattended for assessment and follow up. Againthis is a heterogeneous disorder and is usuallyconsidered to the 'mild' because of the reten-tion of normal IQ by affected patients. Thedisorder should not, however, be consideredbenign. In addition to relatively easily treatedearly complications such as ear, nose, andthroat disease or carpal tunnel syndrome thereare some more serious potential problems.Presentation with endocardial fibroelastosis'2or cardiomyopathy'3 has been reported, and inaddition cervical myelopathy is known tooccur.14 The most serious complication, asthere is no effective treatment, is the develop-ment of progressive, diffuse airway narrowingleading to cor pulmonale and death in lateteens or early twenties.

In theory, MPS VI is the one mucopoly-saccharidosis most suitable to 'curative' treat-ment by enzyme replacement, as the centralnervous system is not affected. There is also anexcellent feline animal model which makesassessment of such treatment appropriatebefore human trials.

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The mucopolysaccharidoses: a clinical review and guide to management 267

MUCOPOLYSACCHARIDOSIS TYPE VII,3-GLUCURONIDASE DEFICENCY (MPS VII, SLY'SDISEASE)This disorder is extremely rare and no affectedpatients have been seen. Indeed, in our labora-tory where we receive annually over 1000blood samples for lysosomal enzyme assay andover 500 urines for mucopolysaccharide analy-sis we have encountered this disorder on onlytwo occasions in the last 10 years. The pheno-type of affected patients is again very variableand ranges from presentation with hydropsfetalis to a relatively mild Hurler phenotypepresenting in adult life.

OTHER DISORDERSWhile not the purpose of this review it shouldbe noted that there are a number of storagedisorders which produce a phenotype notdissimilar to the mucopolysaccharidoses. Inaddition to the patients outlined above we havealso seen and assessed 20 patients with mucoli-pidosis II and III, eight patients with manno-sidosis (5a and 31-mannosidase deficient),and one with sialic acid storage disease. Allpresenting initially as possible mucopolysac-charidosis patients.

DiscussionThe mucopolysaccharidoses are a group ofdevastating disorders and parents need con-siderable support in dealing with an affectedchild. The mucopolysaccharidoses society* hasoffered many parents and affected individualsconsiderable help as well as raising significantsums of money for research.A sound understanding of the phenotypic

possibilities within each subgroup allows for alogical approach to management which isinevitably multidisciplinary. The paediatricianshould play a lead part in this process and

coordinate services for affected patients. Thedisorders should no longer be regarded as'untreatable' as quality of life for manyindividuals can be greatly improved after rela-tively simple procedures.

Finally, it is important to remember thatthese are genetic disorders. First trimesterprenatal diagnosis is possible for all of the sub-types.Thanks to Professor John Hopwood and colleagues, depart-ment of chemical pathology, Adelaide Children's Hospital, formolecular analyses on many patients.*The Society for Mucopolysaccharide Diseases, 55 Hill

Avenue, Amersham, Bucks HP6 5BX.

1 Hopwood JJ, Morris CP. The mucopolysaccharidoses:diagnosis, molecular genetics and treatment. Mol BiolMed1990; 7: 381-404.

2 Belani KG, Krivit W, Carpenter BLM, et al. Children withmucopolysaccharidosis: perioperative care, morbidity, mor-tality, and new findings. J Pediatr Surg 1993; 28: 403-10.

3 Diaz JH, Belani KG. Perioperative management of childrenwith mucopolysaccharidoses. Anesth Analg 1993; 77:1261-70.

4 Sjogren P, Pedersen T, Steinmetz H. Mucopoly-saccharidoses and anaesthetic risks. Acta AnaesthesiolScand 1987; 31: 214-8.

5 Scott HS, Nelson PV, Cooper A, Wraith JE, Hopwood JJ,Morris CP. Mucopolysaccharidosis type I (Hurler syn-drome): linkage disequilibrium indicates the presence of amajor allele. Hum Genet 1992; 88: 701-2.

6 Donaldson MDC, Pennock CA, Berry PJ, Duncan AW,Cowdrey JE, Leonard JV. Hurler syndrome with car-diomyopathy in infancy. J Pediatr 1989; 114: 430-2.

7 Wraith JE, Alani SM. Carpal tunnel syndrome in themucopolysaccharidoses and related disorders. Arch DisChild 1990; 65: 962-3.

8 Scheie HG, Hambrick GW, Bames LA. A newly diagnosedforme fruste of Hurler's disease (gargoylism). Am JOphthabnol 1962; 53: 753-69.

9 Bunge S, Steglich C, Zuther C, et al. Iduronate-2-sulfatasegene mutations in 16 patients with mucopolysaccharidosistype II (Hunter syndrome). Human Molecular Genetics1993; 2: 1871-5.

10 Cleary MA, Wraith JE. Management of mucopolysacchari-dosis type III. Arch Dis Child 1993; 69: 403-6.

11 McKusick VA. The mucopolysaccharidoses. Heritable disor-ders of connective tissue. 4th Ed. St Louis: Mosby, 1972:598.

12 Fong LV, Menahem S, Wraith JE, Chow CW. Endocardialfibroelastosis in mucopolysaccharidosis type VI. ClinCardiol 1987; 10: 362-4.

13 Hayflick S, Rowe S, Kavanaugh-McHugh A, Olson JL,Valle D. Acute infantile cardiomyopathy as a presentingfeature of mucopolysaccharidosis VI. J Pediatr 1992; 120:269-72.

14 Banna M, Hollenberg R. Compressive meningeal hyper-trophy in mucopolysaccharidoses. AJNR 1987; 8: 385-6.