TY - JOUR
T1 - Genetic assessment in primary hyperoxaluria
T2 - why it matters
AU - Mandrile, Giorgia
AU - Beck, Bodo
AU - Acquaviva, Cecile
AU - Rumsby, Gill
AU - Deesker, Lisa
AU - Garrelfs, Sander
AU - Gupta, Asheeta
AU - on behalf of the OxalEurope Consortium/Erknet Guideline Workgroup On Hyperoxaluria
AU - Bacchetta, Justine
AU - Groothoff, Jaap
N1 - Funding Information: Other members of the Oxaleurope/Erknet workgroup on Clinical Practice Recommendations for Primary Hyperoxaluria for their input: Olivia Boyer, Rimante Cerkauskine, Shabbir Moochhala, Luitzen Groen, Bertrand Knebelmann, Manuel Ferraro, Jovana Putnik, Bhaskar Somani, and Agnieska Prytula. Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.
AB - Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.
KW - AGXT
KW - GRHPR
KW - Genetics
KW - HOGA1
KW - Primary hyperoxaluria
UR - http://www.scopus.com/inward/record.url?scp=85131864421&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00467-022-05613-2
DO - https://doi.org/10.1007/s00467-022-05613-2
M3 - Review article
C2 - 35695965
SN - 0931-041X
JO - Pediatric nephrology (Berlin, Germany)
JF - Pediatric nephrology (Berlin, Germany)
ER -