Thesis (MSc)--Stellenbosch University, 2000. / 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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/51997 |
| Date | 03 1900 |
| Creators | Vergotine, Joseph Vincent |
| Contributors | Kotze, M. J., De Jong, G., Stellenbosch University. Faculty of Medicine & Health Sciences . Dept. of Pathology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | [104] p. : ill. |
| Rights | Stellenbosch University |
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