Thesis (MScMedSc)--University of Stellenbosch, 2011. / ENGLISH SUMMARY: Background: Primary immunodeficiency disorders (PID) disrupt the proper functioning of the immune
system. The prototypic PID is X-linked Agammaglobulinemia (XLA). This disorder is caused by mutations
in the Bruton tyrosine kinase (Btk) gene and results in an arrest in B cell development which leads to a
profound reduction of all classes of serum immunoglobulins (i.e antibodies). Patients with a lack of
antibodies experience recurring bacterial infections during early childhood that can be fatal if not treated.
Intravenous gammaglobulin replacement therapy (IVIg) is the standard treatment for XLA. It provides
passive immunity thereby reducing the number and severity of infections as well as limiting many of the
infectious complications. Early detection and treatment of XLA allows affected individuals to live a
relatively normal life.
Objective: The purpose of this study was to determine the molecular basis of XLA in South Africa using a
direct sequence-based method to detect abnormalities in the Btk gene to aid clinical diagnosis of the
disease.
Methods : Male patients with a clinical diagnosis of XLA were included in this study. Genetic analysis
was used to explore the exonic region of the Btk gene of 5 unrelated male patients and compared to 10
healthy controls. Family members were followed up to determine carrier status, where possible.
Results: Mutational analysis revealed Btk abnormalities in 4 of the 5 patients leading to a definitive
diagnosis of XLA. Two of the three mutations found in this study have been previously described while
one mutation appears to be novel. The novel mutation is a one base pair deletion in exon 16 which leads to
the truncation of the Btk protein. Despite the clinical findings suggestive of XLA, no mutation was
identified in the exonic region of the Btk gene of the remaining patient, indicating that this patient might
have a different form of PID. Maternal follow-up confirmed the maternal inheritance pattern as all mothers
screened were carriers of the Btk mutation present in the affected individual.
Discussion :
Using a direct sequence-based method abnormalities were identified in the Btk gene of three patients.
Molecular diagnosis coupled to clinical history of the patient provides a definitive XLA diagnosis. This
study supports the use of molecular techniques in the diagnosis of PID and underlines the synergy that
could be possible in a clinical setting. / AFRIKAANSE OPSOMMING: Agtergrond: Primêre immuungebrek siektes (PIGS) word gekenmerk aan ‘n gebrek aan teenliggame in
die immuunsisteem wat lei tot herhaalde infeksies in jong kinders wat fataal kan wees indien dit nie
vroegtydig behandel word nie. Die prototype van die bekende PIGS is X-gekoppelde Agammaglobulinemia
(XGA). Die siekte word veroorsaak deur mutasies in die Bruton Tirosien kinase (Btk) geen en lei tot ʼn
stilstand in B sel ontwikkeling en gevolglik ʼn vermindering van alle klasse van serum immuunoglobulins
(teenliggaam). Intraveneuse gammaglobulien vervangingsterapie(IVIg) is die standaard behandeling vir
XGA. Dit voorsien passiewe immunitiet en gevolglik verminder dit die getal en erns van infeksies en
beperk baie van die aansteeklike komplikasies. Vroeë diagnose en behandeling van XGA laat toe dat
geaffekteerde individue ʼn relatiewe normale lewe ly.
Doel: Die doel van hierdie studie is om die molekulêre basis van XGA in Suid Afrika te ondersoek, deur
gebruik te maak van direkte volgorde bepaling van die Btk geen in die hoop om die kliniese diagnose van
die siekte aan te help.
Metode : Manlike pasiente met ‘n kliniese diagnose wan XGA was by die studie ingesluit. Genetiese
analise was gebruik om die “exonic” omgewing van die Btk geen te ondersoek van 5 onverwante manlike
pasiente en vergelyk teenoor 10 gesonde kontrole. Waar moontlik was familie lede ogevolg om draers te
bepaal.
Resultaat: Mutasies in die Btk geen is geidentifiseer in 3 van die 4 pasiente, klinies gediagnoseer meet
XGA. Die mutasies sluit 2 reeds beskryfde variante in en een nuwe mutasie, ‘n een basis paar delesie in
ekson 16 van die Btk geen, Ten spyte van die kliniese profiel suggestief van XGA in die 5de pasient, was
geen mutasies geidentifiseer in die “exconic” omgewing van die Btk geen nie, dit kan moontlik toegeskryf
word aan die teenwoordigheid van ‘n ander vorm van PIGS in hierdie pasient. Opvolg analise op die DNA
van die moeders van die pasiente het die moederlike oorerwings patroon van die siekte bevestig aangesien
al die moeders draers van die geidentifiseerde mutasie in die Btk geen van die gaffekteerde individu was.
Gevolgtrekking: Genetiese analise van die Btk geen blyk ʼn sensitiewe en spesefieke metode te wees om
individue met XGA te diagnoseer. Hierdie studie ondersteun die gebruik van molekulêre metodes in die
diagnose van PIGS en beklemtoon die moontlike sinergie wat kan bestaan tussen hierdie tipe benadering in
die kliniese omgewing. / National Research Foundation / National Health Laboratory Services : Pathology Research Development Grant of NHLS Research Trust Grants
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/6476 |
| Date | 04 March 2011 |
| Creators | Leo, Melanie Joy |
| Contributors | Esser, Monica, Scholtz, Charlotte, Bouic, Patrick, University of Stellenbosch. Faculty of Health Sciences. Dept. of Pathology. Medical Microbiology. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 63 p. : ill. (some col.) |
| Rights | University of Stellenbosch |
Page generated in 0.002 seconds