The MED-PED project : presymptomatic diagnosis in families with disease- related LDL receptor gene mutations

Vergotine, Joseph Vincent (2000-03)

Thesis (MSc)--Stellenbosch University, 2000.

Thesis

ENGLISH ABSTRACT: Familial hypercholesterolaemia (FH) contributes significantly to the high death rate from cardiovascular disease worldwide. FH is a common autosomal co-dominant disease characterised by raised cholesterol levels and premature coronary heart disease (CHD). Whilst these features usually are very prominent in homozygotes the clinical diagnosis of heterozygotes is complicated by variable phenotypic expression. Specific founder genes in the low-density lipoprotein receptor (LDLR) gene have increased the prevalence of FH in South African Afrikaners, Indians, Jews and Coloureds, and screening for these known mutations allows unequivocal diagnosis of FH-affected individuals. The systematic molecular analysis of FH resulted in the identification of at least ten founder-type LDLR gene mutations among the 56 different gene defects described to date in the diverse South African population. DNA screening of 792 at-risk family members for the FH-related mutations identified in 379 index cases, allowed accurate disease diagnosis in an additional 340 relatives and exclusion of the relevant mutation in 452 individuals. This effort forms part of the MED PED FH initiative, a collaborative project to "Make Early Diagnosis and Prevent Early Deaths in MEDical PEDigrees with FH". Evaluation of clinical criteria versus DNA diagnosis of three founder-related mutations (D154N, D206E and V408M) in the South African population demonstrated that the sensitivity and specificity of diagnoses, based on total cholesterol values measured in family members of index cases recruited for this study, were 88% and 77%, respectively. A population-directed DNA diagnosis of FH is therefore justified in South Africa on a routine basis, since expression of the defective gene measured in biochemical tests does not allow accurate diagnosis of FH in all cases. The application of mutation detection was illustrated by prenatal diagnosis of FH performed for a couple who are both heterozygous for the most common Afrikaner mutation, D206E. The mutation was absent in the foetus and a normocholesterolaemic infant was born. Prenatal diagnosis of FH, aimed at the detection of homozygous cases, is particularly applicable in populations and families with molecularly defined LDLR gene mutations. The MED-PED approach resulted in accurate diagnosis and subsequent treatment of FH in more patients, and referral to lipid clinics where they could receive the intensive care their condition justifies. Molecularly diagnosed FH patients will be the first to benefit from future treatment approaches based on mutation type.

AFRIKAANSE OPSOMMING: Familiële hiprcholesterolemie dra grootliks by tot die wêreldwye hoë sterftesyfer van kardiovaskulêre siekte. FH is 'n algemene outosomale ko-dominante siekte wat gekenmerk word deur verhoogde cholesterolvlakke en vroeë koronêre hartsiekte. Terwyl hierdie kenmerke prominent is in homosigote, word die kliniese diagnose van heterosigote bemoeilik deur variasie in fenotipiese uitdrukking. Spesifieke stigtergene in die lae-digtheids lipoproteien reseptor (LDLR) geen het die voorkomssyfer van FH verhoog in Suid Afrikaanse Afrikaners, Indiërs, Jode en Kleurlinge. Sifting vir hierdie bekende mutasies maak akkurate diagnose van FH geaffekteerde individue moontlik. Die sistematiese molekulêre analise van FH het aangetoon dat ten minste tien van die 56 verskillende geen defekte wat tot dusver beskryf is in die Suid-Afrikaanse populasie stigtertipe LDLR geen mutasies is. DNA sifting van 792 familielede vir die FH-verwante mutasie in 379 indeksgevalle geïdentifiseer is, het akkurate diagnose moontlik gemaak in 340 addisionele familielede, en uitsluiting daarvan in 452 individue. Hierdie poging vorm deel van die MED-PED FH ("Make Early Diagnosis and Prevent Early Deaths in MEDical PEDigrees with FH) inisiatief. Evaluering van kliniese kriteria teenoor DNA diagnose van drie stigter verwante mutasies (D154N, D206E en V408M) in die Suid Afrikaanse populasie het getoon dat die sensitiwiteit en spesifisiteit van die diagnose, wat gebasseer is op totale cholesterol waardes in familielede van indeksgevalle, onderskeidelik 88% en 77% was. 'n Populasie gerigte DNA diagnose van FH is dus geregverdig in Suid-Afrika op "n roetine basis, omdat die defektiewe geen nie altyd in biochemiese toetse uitgedruk word nie. Die waarde van mutasie opsporing is geillustreer deur 'n voorgeboortelike diagnose van FH wat aangevra is vir ouers wat beide heterosigoties is vir die mees algemene Afrikaner mutasie, D206E. Die mutasie was afwesig in die fetus en 'n normocholesterolemiese baba is gebore. Voorgeboortelike diagnose van FH, wat gemik is op die opsporing van homosigotiese gevalle, is veral van toepassing in populasies en families met bekende LDLR geen mutasies. Die MED-PED benadering het gelei tot akkurate diagnose en daaropvolgende behandeling van FH in meer pasiënte, en verwysings na lipiedklinieke waar hulle intensiewe aandag kan geniet. Molekulêre gediagnoseerde FH pasiënte sal die eerste wees om baat te vind by toekomstige behandeling wat moontlik gebasseer sal word op mutasie status.

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