#5731 INTRAFAMILIAL HETEROGENEITY AND IMPACT OF FAMILY SCREENING IN PRIMARY HYPEROXALURIA TYPE 1
Authors: Deesker Lisa , Karacoban Hazal , Metry Ella , Groothoff Jaap 
Published: June 2023

Background and Aims

Primary hyperoxaluria is a rare genetic disease, caused by an autosomal recessive mutation of the AGXT gene. Clinical variability in outcome is reported within families with primary hyperoxaluria type 1 (PH1) with identical genotypes, leading to the question which differences in the disease course between affected family members can be attributed to environmental factors and which to early diagnosis or therapy. The limited research on this subject results into prognostic challenges and leads to difficult decision-making concerning the timing of transplantation and therapy. Therefore, the objective of this study was to determine whether and to what extent intra-familial heterogeneity is present, based on a clear definition of intra-familial heterogeneity in PH1 and to analyse the impact of therapeutic intervention and early diagnosis via family screening on the prognosis of siblings.

Method

A retrospective registry study was performed using data from the OxalEurope registry. All families with PH1 were identified and analyzed. A six-point PH1 scoring system was developed to calculate the heterogeneity score within a family, based on the clinical outcome of siblings (Table 1). A score ≥2 was considered as significant intra-familial heterogeneity. Assessment of the impact of family screening was conducted by stratification of the patients based on family screening and symptoms. The Fisher-Freeman-Halton exact test, Mann-Whitney U test, Kruskal Wallis test and Kaplan Meier analysis were used for statistical testing.

Results

A total of 88 families were included in this study, including a total of 193 patients with PH1. The median (IQR) follow-up time was 7.8 (1.9-17) years. Family screening was conducted in most families (77%), although not all. Intra-familial heterogeneity was found in 38 (43%) families. A (partly) B6-responsive mutation did not lead to a significant difference in intra-familial heterogeneity score. In more than half of the families (54%), affected siblings had a better outcome than the index case and in 67% of families one or more cases of kidney failure occurred. Asymptomatic siblings had a significant better clinical outcome compared to symptomatic siblings and index cases based on clinical outcome score (p&lt;0.001). Kaplan-Meier analyses (Figure 1) revealed that index cases reached kidney failure at an earlier age and earlier in follow-up compared to siblings (Log-rank, p&lt;0.0001).

Conclusion

Intra-familial heterogeneity is found in nearly half of families with PH1. These findings confirm that intra-familial heterogeneity is present in PH1, in line with previous reports. Asymptomatic siblings found by family screening had a significant better outcome based on clinical outcome score and kidney survival, substantiating the benefit of family screening. Although the exact cause of heterogeneity in PH1 could not be identified, family screening is essential and strongly recommended since it may improve kidney survival in siblings.