MSc (Med)(Genetic Counselling), Faculty of Health Sciences, University of the Witwatersrand / Autosomal recessive polycystic kidney disease (ARPKD; MIM263200) is a severe recessively
inherited disease of the kidneys and biliary tract, with an incidence of approximately 1 in
20000 in non-isolated populations. It has a variable clinical spectrum from neonatal demise (in
30-50%) to survival into adulthood. ARPKD is caused by mutations at a single locus,
polycystic kidney and hepatic disease 1 (PKHD1), with over 270 pathogenic mutations
described to date. The high rate of compound heterozygosity in affected individuals has made
genotype-phenotype correlations difficult. A common missense mutation, p.M627K, in exon
20 of PKHD1 was identified previously on the majority of ARPKD disease associated alleles
in the Afrikaans population of South Africa suggesting the presence of a founder effect.
The aim of this study was to describe the clinical phenotype of ARPKD in Afrikaans speaking
individuals found to be homozygous for the common mutation, and to compare this phenotype
to previously described cohorts of patients with ARPKD, known to harbour a spectrum of
mutations. This descriptive study used retrospective data collected from records of patients
with ARPKD at Johannesburg and Pretoria Academic Hospitals. Twenty seven individuals
from 24 families were included in the study.
Marked clinical variability was demonstrated within this subject group supporting the
limitation of genotype-phenotype correlation described worldwide. ARPKD was diagnosed at
a median age of 27 days, older than a North American cohort (NAC) born after 1990 (median
age of 1 day). The majority (93%) of subjects in this study were diagnosed with chronic renal
v
insufficiency (CRI) and hypertension (HT), indicating the renal morbidities to be more
common than noted in previous studies, but occurring at a later median age (1.4 years vs 13.5
days in the NAC). This may indicate a trend toward milder expression of renal morbidities in
the present study. Portal hypertension was also diagnosed more frequently (81%) than in
previous studies but at a younger median age (1.3 years vs 2.8 years), although with similar
complication rates. Overall statistical correlation was found between the renal and hepatic
related morbidities in this study, indicating that progression of the condition is not organ
specific. A survival rate of 89% at one year is comparable to previous studies with similar
patient ascertainment.
This cohort represents the largest series of patients affected by ARPKD with a common
mutation, described to date. The findings will provide for more accurate, specific and
informative genetic counselling in families with ARPKD and may present a resource for
future studies of modifier genes and environmental influences on the phenotypic expression of
ARPKD.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/8541 |
| Date | 24 August 2010 |
| Creators | Lambie, Lindsay Ann |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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