Report of a mucopolysaccharidosis occurring in Australian

Journal ofMedical Genetics, 1978, 15,455-461

Report of a mucopolysaccharidosis occurringin Australian aborigines1

H. R. TAYLOR, F. C. HOLLOWS, J. J. HOPWOOD, AND E. F. ROBERTSON

From the National Trachoma and Eye Health Programme; Melbourne University Department ofOphthalmology; University ofNew South Wales Department ofOphthalmology; and the Department ofChemical Pathology, Adelaide Children's Hospital, Australia

SUMMARY The first 2 reported cases of a mucopolysaccharidosis occurring in an Australianaboriginal family are presented. Though these children had the characteristic morphological featuresof the Hurler syndrome, enzyme assay of cultured fibroblasts showed normal levels of a-L-iduronidaseand decreased activity of arylsulphatase B. Thus, they represented the Hurler syndrome clinically,while they had the enzyme defect of the Maroteaux-Lamy syndrome, and they may represent a newsevere form of the Maroteaux-Lamy syndrome. The parents of these children were first cousins.Though the children were not full blood aborigines, examination of the pedigree indicates, that the geneoriginated in the common aboriginal family.

The Hurler syndrome, or mucopolysaccharidosis(MPS) IH, is a well-recognised, but uncommon, reces-sively inherited abnormality. Children affected by ithave a characteristic appearance and have a deficiencyof the enzyme a-L-iduronidase. It causes progressivemental and physical deterioration in affected childrenand death usually occurs by the age of 10. Othermucopolysaccharidoses, such as the Maroteaux-Lamysyndrome (MPS VI), are even less common, but theyalso have their own characteristic morphological andbiochemical features. These diseases share the com-mon feature of excessive urinary mucopoly-saccharide, increased levels of dermatan sulphate,heparan sulphate, or keratan sulphate being found.This paper documents 2 Australian aboriginal chil-dren who had the characteristic morphologicalfeatures of the Hurler syndrome and biochemicalevidence of a mucopolysaccharide disorder. Not onlyare they the first Australian aborigines to be describedwith a mucopolysaccharide disorder, but theyrepresent a new form of MPS VI.

The clinical findings of these cases of MPS are pre-sented with preliminary biochemical and enzymeassay findings. The origin of the gene mutation is dis-

'This study was sponsored by the Royal Australian College of Ophthalmol-ogists, and funded by the Commonwealth Department of Health under theprovisions of the National Health Act.

Received for publication 29 November 1977

cussed and the pedigree traced. The proband wasidentified during eye examinations performed by theNational Trachoma and Eye Health Programme.

Report offamily

The proband is a 5-year-old boy. He lives in theNeppabunna area of north-eastern South Australia.His parents are first cousins once removed, butbelong to different sub-groups of the Gudnamutja tribe(Fig. 1). He was reported to have been a normalinfant, but his parents noted that from the age of 1 yearhe had become mentally slow and his abdomen hadswollen. Until the age of 2 he apparently had normalvision, but thereafter his sight deteriorated. His familyreported that he often seemed to run into objects in hispath. When seen, he had not yet started to speak andwas unable to dress himself.On examination, he was 90 cm tall (<3rd centile)

and weighed 19 kg (50th centile). His head circum-ference was 56 cm (>98th centile) and he hadscaphocephaly. He had a Hurler facies (Fig. 2) with asaddle nose, flared nasal tip, thickened lips, and a largetongue. His teeth were widely spaced and he hadmoderate nasal obstruction; he breathed through hismouth. His neck was short and thick, and he had alarge pendulous abdomen and an umbilical hernia. Hisliver was firm and enlarged, extending 10 cm below thecostal margin. The tip of an enlarged spleen was

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456 Taylor, Hollows, Hopwood, and Robertson

Other abnormalities Q Sex unknown O Examined i MPS disorder U

Fig. 1 Pedigree ofaboriginalfamily containing mucopolysaccharide disorder. Consanguinity ofparents ofaffected

Fig. 2 Proband (V.34) showing many classicalfeatures of the Hurler syndrome.

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A mucopolysaccharidosis occurring in Australian aborigines

children is shown by the heavy line. The division between Aururu and Matherie reflects 2 well-defined sub-tribal groups.

palpable. There were no inguinal herniae or hydro-celes. His ribs were splayed inferiorly and he hadgynaecomastia. A loud systolic murmur maximal atthe left sternal edge was present. His hands were broadwith stubby fingers and some clawing of the 5th fingerof each hand. There was restriction of joint mobility,especially of extension. He had genu valgum and pesplanus. Fine lanugo covered most of his body,especially his face, and coarse hair covered his back.

Ocular examination showed mild bilateraltrachoma, his corneae showing 1 mm of pannus. Finescarring of the tarsal conjunctiva and small tarsalpapillae were present. His corneae also had finespeckled opacities in the deeper layers which weremore marked peripherally. The optic discs were large,pale, and swollen, while the retinal pigmentation wasnormal for his race. Though he responded to light, andcould avoid objects, no accurate assessment of visionwas possible because of his mental retardation.Though clinically he showed profound mental retar-dation, no formal investigation of his mental age waspossible because of the field conditions. His hearingwas normal.

Further questioning of the proband's parentsrevealed that an- elder sister (V.3 1), who had recentlydied, had suffered from the same condition. Review ofhospital records showed that she had first presented atthe age of 18 months with gastroenteritis, and thediagnosis of the Hurler syndrome was made. Shepresented again at the age of 4 with a mild left-sidedhemiparesis after a fall. At the age of 6, she showedclinical signs of hydrocephalus which was confirmed Fig. 3 (V31) Affected older sister.

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Taylor, Hollows, Hopwood, and Robertson

by air encephalography. This was managed conser-vatively. She also had scaphocephaly, a Hurler facies(Fig. 3), kyphosis, an umbilical hernia, hepatospleno-megaly, and hazy corneae. Radiological examinationshowed the classical changes of dysostosis multiplexusually associated with the Hurler syndrome. Reillybodies were found in her circulating lymphocytes. Shewas finally admitted to hospital at the age of 10 withpneumonia and otitis media. She developed menin-gitis and septicaemia and died.At necropsy, the brain showed the features of

hydrocephalus. The meninges were thickened andoedematous. There was a heavy infiltrate of foamymacrophages and polymorphs. Neurones showinghypoxic and ballooned storage changes were seen. Theneuroglial network was loose and oedematous. Ex-cessive lipofuschin was seen, as was an occasionalZebra body. The pituitary showed numerousvacuolated acidophils.

The heart showed focal myofibrillary fat change andvalvular and perivalvular endocardial fibrosis. Therewere numerous histiocytes in the collagenous valvetissue.The liver showed excessive portal fibrous tissue,

Kupffer cell hyperplasia, and slight centrilobular fattychange. Slight PAS positive material was found afterdigest clearing, and toluidine blue metachromaticmaterial was found in frozen sections.The spleen was depleted of white pulp and had

foamy storage histiocytes. In the kidney, there wasmild tubular fatty change, focal calcification, andprotein casts. The suprarenal gland showed severelipid depletion. There was severe atrophy of thethymus. Growth arrest had occurred at the costo-chondral junctions. The lungs showed the changes ofbronchopneumonia.The proband's younger sister (V.35), aged 18

months, was regarded by the family as a normalinfant. Her height was 77 cm (25th centile). She had abroad saddle nose with nasal obstruction (Fig. 4), buther mouth, tongue, and dentition were normal for age.Her hands and feet were normal, and her joints freelymobile. The ribs were splayed and there was a softsystolic murmur at the left sternal edge. Her adbomenwas protuberant and 6 cm of firm liver was palpable.The tip of the spleen could also be felt. She hadrecently developed an umbilical hernia. No ocularstigmata of MPS were apparent, though she did havetrachoma with follicles in the upper tarsal con-junctiva. Vision and hearing were normal.A female first cousin once removed (IV. 15), aged

38, showed a number of abnormalities. She had beenregarded by her family as slow and 'funny' since theage of 9. She was 147 cm tall and was obese, weighing76 kg. She had a broad saddle nose, hypertelorism,epicanthic folds, a large mouth with irregularly spaced

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Fig. 4 (V.35) Normalyounger sister.

teeth, and a large tongue (Fig. 5). She suffered fromnasal obstruction and sinusitis.

Her neck was short and thick and her hands weresmall, with shortening of the metacarpals and flexiondeformity of the 5th fingers. Joint mobility wasslightly reduced, being more obvious in her wrists. Shehad severe restriction of right shoulder movement withcrepitus, and restricted movement in her left knee andankle. She had genu valgum. The left leg was deformedwith large exostoses at each end of the tibia and fibula.Her feet were broad with webbing of the second andthird toes, and an overriding fourth toe on each foot.The abdomen was pendulous. She had an umbilical

hernia, but no inguinal herniae were present. Therewas a right lower paramedian scar following hysterec-tomy 5 years previously for chronic cervicitis andendometrial polyps. The liver was firm and palpable 7cm below the costal margin. The tip of her spleen wasalso palpable. Her lower ribs were splayed and she hadpoor chest expansion. A loud systolic murmur at theleft sternal edge and a third heart sound were audible.She had fine lanugo, especially on the face and back.She showed moderate mental retardation and herhearing was normal.

Ocular examination showed a mixed astigmatism,which, when corrected, resulted in an acuity of 6/6

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Fig. 5 (IV.15) Facies showing broad saddle nose,hypertelorism, epicanthicfolds, and large mouth.

on the right eye and 6/9 on the left, despite earlycortical lens opacities. Her corneae were clear andbright, apart from a 2 mm trachomatous pannus andHerbert's pits in each eye. She showed moderatescarring of her tarsal conjunctiva and mild papillaeformation.

Examination of hospital records showed thatprevious syphilis serology had been negative. X-rayshad shown exostoses of the right acromion, the rightclavicle, the heads of the radii, the left tibial and fibularheads, and the lower end of the left fibula with tibio-fibular fusion. X-rays confirmed the shortening of allmetacarpals and the fourth metatarsals.

The pedigree for the family (Fig. 1) was con-structed from information supplied by the relativesand where possible was confirmed by local andmission records of births, deaths, and marriages.Included are 262 people.

Apart from the 4 cases presented, another 57 mem-bers of the family were examined, none of whomshowed any stigmata of an MPS disorder, though a9-year-old male cousin (V.38) was deafand dumb. Twogreat-uncles (111.2, 111.3) were said to have been men-

tally retarded and to have died at the ages of 60 and 62without marrying or having children. Those questionedreported no other family members with significantphysical or mental abnormalities. Two stillbirths(V.23, V.24) and 4 deaths in infancy (IV.11, IV.13,IV.63 from diphtheria, and IV.71 from whoopingcough) were noted.

BIOCHEMICAL INVESTIGATIONSUrine and skin biopsies were taken from members ofthe affected family. Peripheral blood leucocytes werealso obtained from the proband. Early morning urinecollections were screened for the presence of muco-polysaccharides (Table 1).

Sequential thin layer chromatography (Humbel andChamoles, 1972) was also performed on the urineobtained from the proband. Dermatan sulphate andheparan sulphate were present in large quantities andchondroitin-4-sulphate was markedly raised. Semi-quantitative estimation of the visualised glycosamino-glycans indicated that dermatan sulphate was themajor component.Enzyme assays were performed on cells grown in

tissue culture (Table 2). The assay for a-L-iduronidasewas based on the breakdown of iduronosyl (3H)anhydromannitol sulphate to (3H) anhydromannitolsulphate (Hopwood and Muller, 1977; Hopwood,1978). Arylsulphatase B was separated electro-phoretically from arylsulphatase A (Rattazzi et al.,

Table 1 Results ofmucopolysaccharide screening ofearly morning urine samples ofproband and hisfamily

Case Age Creatinine Acid AzureA Cetylpridimium(y) (mg/lOOmt) albumin chloride

turbidity turbidity Normal range(mg/f) (mg/g creatinine) (mg/g creatinine)

FatherIV.12 33 116 - - 28 24 Lessthan 110MotherIV.69 32 131 - - 28 55 Lessthan 110Sib V.30 12 137 - - 92 67 Lessthan 150Case2 V.31 10 31 ++ + 217 700 Less than 140SibV.32 8 85 - - 92 108 Lessthan 160SibV.33 4 155 - - 176 114 Lessthan 180Proband V.34 5 76 ++ + 540 710 Less than 175Sib V.35 4j 10 - - 28 280 Less than 400Second cousin IV.13 38 177 - - 98 55 Less than 110Second cousin (2nd specimen) 3 - - 02 67 Less than 110

*For conversion to SI units, 1 mg/100 ml 88-4 pmol/l.

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Table 2 a-L-iduronidase and arylsulphatase B activity inmembers ofthe affectedfamily, normal controls, andpeoplewith either the Hurler or Maroteaux-Lamy syndromes

Cultured skinfibroblasts a-L-iduronldase ArylsulphataseB(pmol/min per mg) (% A & B)

Father IV.12 239,293 -

Mother IV. 69 132,147 79Proband V.34 190,229 12, 14Case 2 V.31 184,281 22, 26, 29Sib V.35 197,222 -Second cousin IV.31 162,155 66Normal range 87-679 (n = 25) 38-84 (n = 12)Hurler range 0.6-4.4 (n= 6) -

Maroteaux-Lamy range - 11-29 (n = 3)Peripheral blood leucocytes

Proband V.34 100 0Normal range 27-134 (n = 24) 12-88 (n = 11)Hurler range 3-5-6 (n = 3) -

Maroteaux-Lamy range - 0 (n = 3)

1973). Some modifications were used to improveseparation and to quantify arylsulphatase B activity asa percentage of arylsulphatase A and B.These tests showed the presence of mucopoly-

saccharides in the urine of the 2 affected children(V.34 and V.3 1). Mucopolysaccharides were notraised in the urine of other family members. Theenzyme studies showed normal a-L-iduronidase levelsand low arylsulphatase B levels in the affectedchildren. Both enzymes were normal in the others.These findings give a biochemical diagnosis ofMaroteaux-Lamy type mucopolysaccharidosis (MPStype VI).

Tests for mucopolysaccharide disorders were nor-mal in the second cousin (IV. 13) (Table 1). Assaysshowed that the activity of the following enzymes inher fibroblast cultures were normal: hexosaminidaseA and B, f-galactosidase, a-galactosidase, a-manno-sidase, a-glucosidase, fl-glucosidase, and,-glucuroni-dase.

Discussion

The mucopolysaccharidoses are well recognised andwell documented disorders of mucopolysaccharidestorage. They are transmitted recessively, with theexception of the Hunter syndrome (MPS II A and B),which is transmitted as an X-linked disorder. Theclinical features, genetics, and biochemical defectshave been comprehensively reviewed by McKusick(1972). MPS, such as the Hurler syndrome, havebeen noted in many different races, but until nownone has been reported as occurring in the Australianaborigine.The exact nature of the defect ofMPS storage in the

cases presented here is not yet known, though the pres-ence of heparan sulphate, dermatan sulphate, and

Taylor, Hollows, Hopwood, and Robertson

raised levels of chondroitin-4-sulphate in the urineconfirms that such a disorder exists.The results of enzyme analysis suggest the diag-

nosis of MPS VI, though heparan sulphate is notusually found in the urine in this condition. It is,however, present in MPS IH.

Children with MPS VI differ from those presentedin several important clinical features. Most signifi-cantly, they have normal intelligence and in some caseseven better than normal. The cases presented hereshowed severe mental retardation. Those affected withMPS VI are usually taller and have a longer life span.Morphologically, these cases showed more of theclassical features of MPS IH rather than those of MPSVI. In particular, they had the coarse facies andfeatures of the Hurler syndrome. The radiologicalfeatures were also suggestive of MPS IH, though inseverely affected MPS VI patients the changes may beindistinguishable from MPS IH.MPS VI is known to occur in 2 forms; a mild form,

VIB, which clinically resembles MPS IS, and a moresevere form, VIA (McKusick, 1972). If the childrenpresented here are of an MPS VI type then they repre-sent an even more severe form of MPS VI thanpreviously reported.A deficiency of arylsulphatase B is also found in

metachromatic leucodystrophy variant with multiplesulphatase deficiencies. Mucopolysacchariduria mayalso be present. However, the clinical appearance ofthis condition is quite different.The children were not full blood aborigines. The

mother of these children (IV.69) had 15/16 aboriginalblood. She had a European maternal great-great-grandfather (L.7). The father (IV. 12) had 7/8aboriginal blood, since his maternal great-grandfatherwas Indian (II. 1). These children, therefore, had 29/32aboriginal blood. It is suggested that the geneoriginated in the common full blood aboriginal familyas the parents are first cousins once removed. Thoughthe 2 families intermarried on 6 occasions, only onefamily has affected children.

The young child (V.35) showed the difficulty inrecognising an MPS disorder in aborigines. TheAustralian aborigine tends to have a broad saddle noseand a large mouth. Protuberant abdomens and hepato-megaly are common as a result of poor nutrition.Despite these racial and environmental effects, theproband had a classical 'Hurler' appearance, and waseasily recognised as being different from his sibs.

The 38-year-old female second cousin (IV.15)showed a number of clinical characteristics of an MPSdisorder, though none of the biochemical charac-teristics were found. Other tissue storage diseases werealso excluded biochemically. The multiple exostosesshe had may represent this common dominant trait,but no other family member was found with multiple



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exostoses. The exact nature of her disability is not yetknown.

The 2 children presented in this report clinically hada mucopolysaccharidosis which was confirmed bythe presence of increased amounts of mucopoly-saccharide in their urine. The clinical features are

almost identical to those of the Hurler syndrome, butnormal a-L-iduronidase activity and decreased aryl-sulphatase B activity were'found in cultured fibro-blasts, suggesting the Maroteaux-Lamy syndrome.Further enzyme studies may pinpoint their metabolicdeficiency.The authors wish to thank Professor D. Danks, RoyalChildren's Hospital, Melbourne for his advice; themembers of the National Trachoma and Eye HealthProgramme for their co-operation; and particularly,the members of the aboriginal communities for theirassistance.

Hopwood, J. J. (1978). Carbohydrate Research. (In the press.)Hopwood, J. J., and Muller, V. (1977). a-L-iduronidase activity

measured using natural substrates derived from heparin. UppsalaJournal ofMedical Science, 82, 134. (Abst.)

Humbel, R., and Chamoles, N. A. (1972). Sequential thin layerchromatography of urinary acidic glycosaminglycans. ClinicaChimica Acta, 40,290-293.

McKusick, V. A. (1972). Heritable Disorders of Connective Tissue,4th ed., pp. 531-664. Mosby, St. Louis.

Rattazzi, M. C., Marks, J. S., and Davidson, R. G. (1973).Electrophoresis of arylsulphatase from normal individuals andpatients with metachromatic leukodystrophy, American JournalofHuman Genetics, 25,310-316.

Requests for reprints to Dr H. R. Taylor, The WilmerInstitute, The Johns Hopkins Hospital, 600 N. WolfeStreet, Baltimore, Maryland 21205, USA.

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Report of a mucopolysaccharidosis occurring in Australian