Coetzee, Gerhard A.

Kotze, Maritha J.

Langenhoven, Elzet

Rubinsztein, David C.

van der Westhuyzen, Deneys R.

English

AJOL - African Journals Online

in the central Cape had high stillbirth, ENNO and LBW rates,which suggest both poor living conditions and inadequateperinatal care. Of interest are the eastern Cape regionswhere the stillbirth rate is high in spite of relatively few LBWinfants. The reasons for this are uncertain, but intrapartumdeaths due to hypoxia in well-grown infants may becommon.The two regions with the highest PMRs were LowerOrange River and Port Elizabeth-Uitenhage. The LowerOrange River region is an area that stretches over a greatdistance with a low population density and only 6 889deliveries. A probable explanation for the high PMR is theinaccessibility of health services in this region. In contrastPort Elizabeth-Uitenhage, which is a densely populatedregion, has a large, unemployed community and manymigrants seeking care from limited services.Having identified regions with many LBW infants and highPMRs, further studies are needed to document the causesand plan appropriate intervention policies. A shortcoming ofthe present study was that data were collected according tothe place of birth and not the place of residence. The resultscould therefore be influenced by patterns of migration andreferral. Coding data according to home addresses wouldbe of greater value but more difficult to collect. All infantsweighing between 500 and 1 000 g should also be includedin future surveys. These additional data would increase themortality rates, especially the stillbirth rate.In conclusion, a survey of perinatal mortality within theplanning regions of the Cape Province reveals widegeographical differences and a pattern expected in adeveloping country. In addition, the survey identifies regionswhere particular attention must be paid to living conditionsand perinatal health services.We would like to thank the staff of all the hospitals and clinicsin the Cape Province who helped with the collection of the datapresented in this study.REFERENCES1. Van Coerverden de Groat HA, Oavey OA, Howland RC. The Peninsula Maternity andNeonatal Service. S AIr Med J 1982; 61: 35-36.2. New Health Regions for South Africa. Epidemiological Comments 1992; 19: 59-68.3. World Health Organisation. Division of Family Medicine. The incidence of low birthweight: a critical review of available information. World Health Stat 0 1980; 33(3):197-224.4. World Health Organisation. Social and Biological Effects on Perinatal Mortality Vol. 1(Report on an international comparative study sponsored by the World HealthOrganisation). Geneva: WHO. 1978.5. Alberman E. Why are stillbirth and neonatal mortality rates continuing to fall? Br JObslet Gynaecol 1985; 92: 559-564.6. World Health Organisation. World Health Statistics Annual. Vol. 1. Geneva: WHO,1977.Accepted 5 Apr 1994.SAMJARTICLESFamilial defectiveapolipoprotein-B is rare inhypercholesterolaemicSouth African Afrikaners,coloureds and Indians-David C. Rubinsztein, Gerhard A. Coetzee, DeneysR. van der Westhuyzen, Elzet Langenhoven,Maritha J. KotzeThe frequency of familial defective apolipoprotein B-100(FOB) was assessed among hypercholesterolaemicAfrikaners, coloureds and Indians. Patients selected forscreening did not carry any of the founder or commonLOL-receptor mutations known to be associated withthese groups. No FOB was detected and the mutation istherefore a rare cause of hypercholesterolaemia in theseSouth African populations.S Atr Med J 1995; 85: 355-357.Familial defective apolipoprotein B-100 (FOB) ischaracterised by the presence of LDL particles that carryapolipoprotein B-100 with the arg3500-glu mutation; thesehave a markedly lower affinity for the LOL receptor and arecleared abnormally slowly from the circulation.'Heterozygotes for this disorder present withhypercholesterolaemia and clinical sequelae such asxanthomata with a frequency and severity similar to thatfound in heterozygotes with familial hypercholesterolaemia(FH), a disorder caused by LD.L-receptor mutations!-4 Someindividual cases, however, have been reported in which FOBheterozygotesS and one homozygote· had relativelymoderate hypercholesterolaemia. The incidence of FOB isabout 1/500 - 11700 in North America and Europe.3 Detailedhaplotype analysis of mutant apo B alleles from many FOBindividuals suggests that this is a founder-type mutation thatoccurred only once on an ancestral chromosome.7 Thefrequency of such a mutation in different populations is likelyto be governed by founder effects and random genetic driftand should vary greatly. Indeed this mutation has not beenMedical Research Council/UCT Research Unit for the Cell Biology ofAtherosclerosis, Department of Medical Biochemistry, University ofCape TownDavid C. Rubinsztein. M.B. CH.B.• PH.D.Gerhard A. Coetzee. PHD.Deneys R. van der Westhuyzen. PHD.Department of Human Genetics, University of Stellenbosch,Tygerberg, W. CapeElzet Langenhoven. M.SC.Maritha J. Kotze. PHD.SAMJ VO/lIme 85 No.5 May 1995detected in Finns," Japanese9or Israelis.'o Consequently, inorder to determine the impact of this mutation in SouthAfrica, its frequency was determined in .hypercholesterolaemic Afrikaners, coloureds and Indianswith or without xanthomata.English and Afrikaner descent.4,22 It was impossible to .determine the geographical or genetic origin of the mutationin these two cases.Table I. Summary of South African lipid clinic patients screenedfor FOB'The South African Medical Research Council, Old Mutual, theUniversities of Cape Town and Stellenbosch and the Stella andPaul Loewenstein Trust are thanked for financial support.Ms S. Jones and Ms H. Karjiker provided excellent technicalassistance. Ors A. O. Marais, G. M. Berger, M. C. Rajput,F. Raal, H. Settel and K. Steyn are thanked for providing bloodand clinical information on patients from their lipid clinics.Or P. Talmud is thanked for providing FOB-positive controlsamples.• All patients listed in this table were negative for FOB. .t All Afrikaner and coloured patients were screened for the FH Afrikaner-l, -2 and -3founder mutations prior to analysis for FDB. Coloured patIents were also screened _for FH Cape Town-2. Indian patients were screened for the FH Zambia mutation. .All patients positive for any of these LDL-receptor mutations were excluded from thiSanalysis.*Definite MH (monogenic hypercholesterolaemia) patients had total cholesterol> 7,5 mmol/l or LDL-eholesterol > 5,2 mmol/l together with xanthomata or thickenedAchilles tendons in themselves or a first-degree relative..Type 2a patients had total cholesterol> 7,5 mmol/l or LDL-eholesterol > 5,2 ~mol/land triglycerides < 2,3 mmol/l without xanthomata in themselves Or a first-deg~relative.§ Includes 13 patients screened by Graadt van Roggen et al."The frequencies of FDB and FH in North America andEurope are both about 1/500,3-23 and the two diseases areclinically almost indistinguishable in terms of the presence ofxanthomata.'" In such populations, one would expecttherefore to find equal numbers of FDB and FH alleles inhypercholesterolaemic individuals with xanthomata fromwhich FH patients with common or founder LDL-receptormutations were excluded. Since we detected no suchpatients with FOB, this disorder is probably not as commonin Afrikaners, coloureds and Indians as sporadic FH. Also,because no FOB was detected in patients with type 2Ahyperlipidaemia without xanthomata, it is likely that thefrequency of FOB in these populations is less than 1/500.The possibility exists that FOB does occur with a higherfrequency in these groups, but does not causehypercholesterolaemia or xanthomatosis uniquely. Weconsider this possibility unlikely.Since FDB is a founder-type mutation,' its frequency islikely to vary between different populations. To ourknowledge, FDB has not been detected yet among Finns,"Japanese9or Israelis'o and no studies have been reported forIndians or black Africans. It is possible that this mutationmight have occurred after the events that gave rise to thedifferent racial groups. The absence of FDB in the Afrikanersand coloureds could have arisen from a 'negative' founder-effect that diluted the frequency of this gene in the settlersrelative to their parent European populations. We concludethat FOB is a rare cause of hypercholesterolaemia in theseSouth African populations.MethodsAll patients were unrelated and attended lipid clinics in CapeTown, Durban and Johannesburg. Individuals wereconsidered Afrikaner, coloured or Indian only if both parentsbelonged to that population group. The so-called colouredpopulation of South Africa are of mixed racial descent andhave genes of indigenous Africans and of European andIndonesian settlers. The Indian population is descendedfrom Indian immigrants who arrived in South Africa between1860 and 1911. Blood was taken after informed consent hadbeen obtained, and with ethical approval by the appropriateinstitution.DNA isolation from blood was carried out as described byTalmud et al." FDB was screened for as described byHansen et al. 12 and Tybjaerg-Hansen et al. 13 The FHAfrikaner-1, FH Afrikaner-3 and FH Cape Town-2 mutationswere assayed as described previously."'" The FH Afrikaner-2mutation was detected by means of an amplificationrefractory mutation system (ARMS) polymerase chainreaction assay." All Indian patients were screened for the FHZambia mutation, as described by Rubinsztein et al. 17Results and discussionHypercholesterolaemic South African Afrikaner, coloured andIndian patients were selected for screening for FDB afterindividuals who had anyone of the common or founderLDL-receptor mutations known to be associated with thesegroups'4,'5,17.'9 had been eliminated (Table I). These individualswere classified as having either definite monogenichypercholesterolaemia or type 2A hyperlipidaemia.individuals were considered to have definite monogenichypercholesterolaemia, Le. either FH or FDB, if they hadtotal cholesterol concentrations greater than 7,5 mmol/I orLDL-cholesterol concentrations greater than 5,2 mmol/I,together with xanthomata or thickened tendons inthemselves or in a first-degree relative. Cholesterolconcentrations above these limits are compatible with FH.'oThree founder LDL-receptor mutations, FH Afrikaner-1, -2and -3, account for apprOXimately 90% of the FH inAfrikaners. 14.2' These three mutations and the FH CapeTown-2 mutation have been found in the colouredpopulation (D. J. van der Westhuyzen and M. J. Kotze-unpublished data). Therefore, all patients with thesemutations were eliminated from the study. The only mutationdetected so far in more than one South African Indian familyis FH-Zambia. 17 Similarly, all Indian patients with thismutation were not considered. None of the patients listed inTable I was found to have FDB. Therefore, all patients withdefinite monogenic hypercholesterolaemia are likely to haverare sporadic LDL-receptor mutations. FOB has beendetected in two unrelated families in South Africa of mixedAfrikanerstColouredstIndianstDefinite MH*20§ -86'Type 2a'1123816Volume 85 No.5 May 1995 SAMJ•--REFERENCES1. lnnerarity TL. Mahtey RW, Weisgraber KH, et al. Familial defective apolipoprotein8-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J LipidRes 1990; 31: 1337-1349.2. Rauh G, Keller C, Karmann B, et al. Familial defective apolipoprotein 8-100:clinical characteristics of 54 cases. Atherosclerosis 1992; 92: 233-241.3. Tybjaerg-Hansen A, Humphries SE. Familial defective apolipoprotein 8-100: asingle mutation that causes hyperchoJesteroJemia and premature coronary heartdisease. Atherosclerosis 1992; 96: 91-107.4. Rubinsztein DC. Raal FJ, Settel He, Pilcher G, eoetzee GA, Van der WesthuyzenOR. Characterization of six patients who are double heterozygotes for familialhypercholesterolemia and familial defective apo B-l00. Arteriosclerosis andThrombosis 1993; 13: 1076-1081-5. Davignon J, Dufour R, Roy M, et aJ. Phenotypic heterogeneity associated withdefective apolipoprotein B-100 and occurrence of the familialhypercholesterolemia phenotype in the absence of an LDL-receptor defect withina Canadian kindred. EurJ Epidemio/1992; 8: 10-17.6. Marz W, Ruzicka C, Pohl T, Usadel KH, Gross W. Familial defectiveapolipoprotein B-l00: mild hypercholesterolemia without atherosclerosis in ahomozygous patient. Lancet 1992; 340: 1362.7. Ludwig EH, McCarthy BJ. Haplotype analysis of the human apolipoprotein Bmutation associated with familial defective apolipoprotein B-l00. Am J HumGenet 1990; 47: 712-720.8. Hamalainen T, Palotie A, Aalto-Setala K, Kontula K, Tikkanen MJ. Absence offamilial defective apolipoprotein B-l00 in Finnish patients with elevated serumcholesterol. Atherosclerosis 1990; 82: 177-183.9. Hosking JL, Bais R, Roach PO, Thomas DW. Hypercholesterolemia due to familialdefective apolipoprotein 8-100 in two Australian families (Correspondence). MedJ Aust 1991; 155: 572-573.10. Friedlander Y. Dan EJ, Leitersdorf E. Absence of familial defective apolipoproteinB-l00 in Israeli patients with dominantly inherited hypercholesterolemia and inoffspring with parental history of myocardial infarction. Hum Genet 1993; 91:299-300.11. Talmud P, Tybjaerg-Hansen A, Bhatnagar 0, et al. Rapid screening for specificmutations in patients with clink::al diagnosis of familial hypercholesterolemia.Atherosclerosis 1991; 89: 137-141.12. Hansen PS, ROdiger N, Tybjaerg-Hansen A, Faergemann 0, Gregian N. Detectionof the apo-B-3500 mutation (glutamine for arginine) by gene amplification andcleavage with Msp 1- J Upid Res 1991; 32: 1229-i 233.13. Tybjaerg-Hansen A. Gallagher J, Vincent J, et al. Familial defective apolipoprotein8-100; detection in the United Kingdom and Scandinavia and clinicalcharacteristics of the cases. Atherosclerosis 1990; 80: 235-242.14. Graadt van Roggen FJ, Van der Westhuyzen OR, Marais AD, Gevers W, CoetzeeGA. Low density lipoprotein founder mutations in Afrikaner familialhyperchalesterolemia patients: a comparison of two geographical areas. HumGenet 1991; 88: 204-208.15. Henderson HE, Serger GM8, Marais AD. A new LDL receptor gene deletion in theSouth African population. Hum Genet 1988; 80: 371-374.16. Kotze MJ, Langenhoven E, Theart L, Loubser 0, Micklem A, Oosthuizen CJJ.Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in SouthAfrican coloureds and Afrikaners. S Atr Med J 1995; 85: 357-361 (this issue.)17. Rubinsztein DC, Coetzee GA, Marais AD, Leitersdorf E, Settel HC, Van derWesthuyzen OR. Identification and properties of the proline..-Ieucine mutant LDLreceptor in South Africans of Indian origin. J Lipid Res 1992; 33: 1647-1655.18. Leitersdorf E, Van der Westhuyzen OR, Coetzee GA, Hobbs HH. Two common lowdensity lipoprotein gene mutations cause familial hypercholesterolemia inAfrikaners. J Clin Invest 1989; 84: 954-961.19. Kotze MJ, Langenhoven E, Warnich L, et al. The identification of two low-densitylipoprotein receptor gene mutations in South African hypercholesterolaemics.S Atr Med J 1989; 76: 399-401 .20. Study Group, European Atherosclerosis Society. The recognition andmanagement of hyperlipidaemia in adults: a policy statement of the EuropeanAtherosclerosis Society. Eur Heart J 1988; 9: 571 -600.21. Kotze MJ, Langenhoven E, Warnich L, Du Plessis L, Retief AE. The molecularbasis and diagnosis of familial hypercholesterolemia in South African Afrikaners.Ann Hum Gene! 1991; 55: 115-121-22. Rubinsztein DC. Monogenic hypercholesterolemia in Indians and familialdefective apolipoprotein 8-100. PhD Thesis, University of Cape Town, 1993.23. Goldstein JL, 8rown MS. Familial hypercholesterolemia. In: Scriver CR, BeaudetAL, Sly WS. Valle 0, eds. The Metabolic Basis of Inherited Disease. 6th ed. NewYork: McGraw-HiII, 1989.Accepted 18 Apr 1994.SAMJARTICLESRecurrent LDL-receptormutation causes familialhypercholesterolaemia inSouth African colouredsand AfrikanersM. J. Kotze, E. Langenhoven, L. Theart, O. Loubser,A. Micklem, C. J. J. OosthuizenThree low-density lipoprotein receptor (LDLR) genemutations were previously shown to cause familialhypercholesterolaemia (FH) in up to 90% of affectedAfrikaners. Association of each mutation with a singlechromosomal background provided molecular geneticevidence that the proposed 'founder gene effect' wasresponsible for the high prevalence of FH among whiteAfrikaners. In this study we report the identification of theFH Afrikaner-2 (FH2) mutation, Val408 to Met, in the so-called coloured population of South Africa, a people ofmixed ancestry, with rapid non-radioactive methods formutation detection. Haplotype analysis withpolymorphisms on both sides of the FH2 mutationindicated that the identical LDLR gene mutations found intwo different South African population groups werecaused by independent events at a potential CpGmutational 'hot spot'. The allelic variation giving rise to thedifferent chromosomal backgrounds of the FH2 mutationdoes not affect the properties of the abnormal LDLRprotein product which causes FH in these subjects. Thismutation is thus expected to cause the same severe formof FH in affected coloureds as was previouslydemonstrated in Afrikaners. Detection of mutant LDLRgene alleles in polymerase chain reaction products,directly after gel electrophoresis, now allows accuratepresymptomatic diagnosis of the FH2 mutation in FHpatients from two different South African populationgroups.S Afr Med J 1995; 85: 357-361.Department of Human Genetics, University of Stellenbosch,Tygerberg, W. CapeM. J. Kotze. PHD.E. Langenhoven, M.SC.L Theart, M.SC.O. Loubser, M.SC.A. Micklem. B.SC. HONSC, J. J. Oosthuizen, PH.D.ISAMJ Volume 85 No. 5 May 1995~

Familial defective apolipoprotein-B is rare in hypercholesterolaemic South African Afrikaners, coloureds and Indians

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Familial defective apolipoprotein-B is rare in hypercholesterolaemic South African Afrikaners, coloureds and Indians

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