Syndrome of the month

Journal of Medical Genetics 1988, 25, 415-418

Type I Gaucher diseaseJACK GOLDBLATTFrom the MRC Unit for Inherited Skeletal Disorders, Departments of Human Genetics and Medicine,University of Cape Town Medical School and Groote Schuur Hospital, Cape Town, South Africa.

Type I Gaucher disease, the subject of this article,was initially reported by Gaucher' in 1882 as anon-leukaemic splenic epithelioma. The bio-chemical defect, an autosomal recessively inheritedlysosomal glucocerebrosidase enzyme deficiency,was delineated in 1965,2 3 and more recently the fulllength coding DNA sequence has been cloned andcharacterised.4Gaucher disease is conventionally classified into

three types on the basis of neuronopathic manifesta-tions and the natural course of the disorder.5 Incontradistinction to type I Gaucher disease, types IIand III have a primary neuronopathic infiltrationwith a progressive neurodegenerative course. Thecondition is acute in type II with death in earlychildhood, while type III is a subacute disorder withsurvival into adulthood.

Pathogenesis

The undegraded metabolite accumulates in cells ofthe monocyte macrophage system and hence themajor clinical manifestations result from infiltrationof the speen, liver, and bone marrow. Owing to thevariable rate of substrate deposition, there is a widespectrum of clinical involvement (figs 1 and 2) fromseverely affected infants to asymptomatic octogen-arians. This unpredictable natural history compli-cates genetic counselling and patient management.

Clinical aspects

CLINICAL ONSETInitial modes of presentation include asymptomaticsplenomegaly, complications of pancytopenia owingto hypersplenism, or the orthopaedic sequelae ofbone marrow infiltration. Although designated the'adult' form, the diagnosis is often confirmed inchildhood.

Received for publicaition 8 January 1988.Accepted for publication 13 January 1988.

HAEMATOLOGICALVariable pancytopenia is a consistent feature whichmanifests with a bleeding tendency and symptoms ofchronic anaemia. Despite significant thrombocy-topenia, life threatening bleeding is infrequentbecause of the functional integrity of the residualplatelets.

ORTHOPAEDICSkeletal complications cause considerable disability

FIG 1 A Oyear oldfemale with type I Gaucher disease andmassive hepatosplenomegaly.

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FIG 3 Radiograph offemur showing typical 'Erlenmeyerflask' deformity.

FIG 2 A 28 year old male with type I Gaucher disease andmoderate hepatosplenomegaly.

in the majority of affected persons.6 Early marrowinvolvement is shown radiographically by the typical'Erlenmeyer flask' deformities of the lower femora(fig 3) resulting from expansion of the medullarycavity. Episodes of ischaemic necrosis presentacutely as a 'pseudo-osteomyelitic crisis' or chroni-cally as aseptic necrosis of the femoral heads (fig 4).With disease progression the entire skeleton may beinvolved causing pathological fractures. Althoughretarded growth and development are not charac-teristic of this condition, short stature may occur inthe more severely affected children.

GASTROINTESTINAL

Hepatosplenomegaly, usually massive in extent, isinvariable and only infrequently have asplenome-galic patients been reported. Hepatomegaly is notusually associated with clinical or biochemical fea-tures of hepatic dysfunction until late in the courseof the disorder when portal hypertension maydevelop.

ASSOCIATED FEATURES

Common minor stigmata are ocular pingueculae,which are fleshy, brown, bulbar conjuctival nodules,

and a diffuse yellow-brown dermal hyper-pigmentation.7 Rarely reported complications,particularly in severely affected post-splenectomypatients, include pulmonary and renal dysfunctionfrom substantial Gaucher cell infiltration.

Differential diagnosis

The diagnosis is confirmed by assaying the specificglucocerebrosidase enzyme in lymphocytes, plate-lets, or fibroblasts. Associated features includehistologically typical Gaucher cells, particularly inliver, spleen, or bone marrow, raised serum acidphosphatase and angiotensin converting enzyme,and the characteristic radiographical features. Thesefindings and the deficient enzyme activity dis-tinguish type I Gaucher disease from the numerousinherited and acquired disorders causing hepato-splenomegaly and hypersplenism. Scattered storagecells histologically similar to Gaucher cells are foundin some haematological conditions, such asleukaemia and thalassaemia, but are differentiatedby the normal glucocerebrosidase activity in thesedisorders.

Management and treatment

Enzyme replacement therapy has been unsuccessful

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Type I Galucher disease

FIG 4 Radiograph ofpelvis showing bilateralavascular necrosis offemoral heads withsecondary osteoarthritis.

FIG 5 Radiograph ofpelvis showing right totalhip arthroplasty and avascular necrosis of leftfemoral head.

and allogenic bone marrow transplantation.although potentially curative, is not justifiable in themajority of patients because the risks of the proce-dure outweigh the benefit offered to the mildlyaffected patient. Management is therefore aimed atthe complications consequent on substrate accu-mulation.

HAEMATOL OGICALSplenectomy reverses the pancytopenia, but there isconsiderable controversy concerning the progres-

sion of the extrasplenic manifestations after thisprocedure. In the absence of prospective controlledtrials, the role of splenectomy in the natural courseof the disorder is uncertain. However, as there areno reliable predictive factors to determine whichsubjects are at later risk of orthopaedic complica-tions, a conservative policy concerning splenectomyis advocated. This procedure should be delayed untilthere is life threatening pancytopenia or rarely, inyoung children, because of cardiorespiratory com-promise. Furthermore, if indicated by these criteria,

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Jack Goldblatt

an attempt should be made to perform a partialsplenectomy in the hope of providing a potentialstorehouse for substrate deposition.8

ORTHOPAEDICBone pain requires analgesia, with care to avoidacetylsalicylic acid and non-steroidal anti-inflammatory agents if thrombocytopenia is present.Episodes of 'pseudo-osteomyelitis' resolve spon-taneously over a period of a few days to about twoweeks. Symptomatic therapy consists of bedrest andanalgesia. It is particularly important to differentiatethese episodes from pyogenic osteomyelitis to avoidunnecessary and potentially harmful bone drilling.The chronic sequelae of avascular necrosis offemoral heads with secondary osteoarthritis is man-aged with prosthetic joint replacement (fig 5) withexcellent long term results.9

Genetics

The condition is most prevalent among AshkenaziJews with an estimated carrier rate of 0-04 to 0-0810compared to a carrier rate of 0 0044 in theAfrikaners of South Africa, the highest reportedoccurrence in a non-Jewish community.'t Hetero-zygotes are asymptomatic but enzyme assay isavailable for carrier detection and prenataldiganosis. 12

Future prospects

The isolation of a full length human glucocerebrosi-dase cDNA clone and its introduction with aretroviral vector into human cells in culture showsthe potential for curative gene therapy for type IGaucher disease. 13 Furthermore, this technologyshould facilitate the large scale production of pureglucocerebrosidase enzyme to allow more concertedattempts at enzyme replacement therapy, which haspossibly failed so far because of the paucity ofenzyme obtained by current purification techniques.

My work in connection with Gaucher disease has

been supported by grants from the Medical Re-search Council of South Africa, the MauerbergerFoundation, the Harry Crossley Foundation, andthe University of Cape Town Staff Research Fund.

References

Gaucher PC. De l'epitheliome primitif de la rate, hypertrophieidiopathique de la rate sans leucemie. PhD thesis, Faculte deMedicine, Paris, 1882.

2 Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebro-sides. II. Evidence of an enzymatic deficiency in Gaucher'sdisease. Biochem Biophys Res Commun 1965;18:221-5.

3 Patrick AD. A deficiency of glucocerebrosidase in Gaucher'sdisease. Biochem J 1965;97:17c-18c.Tsuji S, Choudary PV, Martin BM, Winfield S, Barranger JA,Ginns El. Nucleotide sequence of cDNA containing thecomplete coding sequence for human lysosomal glucocerebrosi-dase. J Biol Chem f986;261:50-3.

5 Brady RO, Barranger JA. Glucosylceramide lipidosis:Gaucher's disease. In: Stanbury JB et al, eds. The metabolicbasis of inherited disease. New York: McGraw-Hill, 1983:842-56.

6 Goldblatt J, Sacks S, Beighton P. The orthopaedic aspects ofGaucher disease. Clin Orthop 1978;137:208-14.Goldblatt J, Beighton P. Cutaneous manifestations of Gaucherdisease. Br J Dermatol 1984;3:331-2.

8 Bar-Maor JA, Govrin-Yehudain J. Partial splenectomy inchildren with Gaucher's disease. Pediatrics 1985;76:398-401.

9 Goldblatt J, Sacks S, Dall D, Beighton P. Total hip arthroplastyin Gaucher's disease: long term prognosis. Clin Orthop (inpress).Matoth Y, Chazan S, Cnaan A, Gelernter I, Klibansky C.Frequency of carriers of chronic (type I) Gaucher disease inAshkenazi Jews. Am J Med Genet 1987,27:561-5.Goldblatt J, Beighton P. Gaucher disease in the Afrikanerpopulation of South Africa. S Afr Med J 1979;55:209-10.

12 Grabowski GA, Dinur T, Gatt S, Desnick RJ. Gaucher type I(Ashkenazi) disease: a new method for heterozygote detectionusing a novel fluorescent natural substrate. Clin Chim Acta1982;124:123-35.

13 Sorge J, Kuhl W, West C, Beutler E. Gaucher disease:retrovirus-mediated correction of the enzymatic defect incultured cells. Cold Spring Harbor Symposia on QuantitativeBiology 1986;LI: 1041-6.

Correspondence and requests for reprints to Dr JGoldblatt, MRC Unit for Inherited Skeletal Dis-orders, Department of Human Genetics, Universityof Cape Town Medical School, Observatory 7925,South Africa.

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