Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene

Clinical Biochemistry, University College London (UCL) Hospitals National Health Service (NHS) Trust, London, UK.
Human Mutation (Impact Factor: 5.05). 06/2009; 30(6):910-7. DOI: 10.1002/humu.21021
Source: PubMed

ABSTRACT Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine:glyoxylate aminotransferase (AGT) enzyme, encoded by the AGXT gene. The disease is manifested by excessive endogenous oxalate production, which leads to impaired renal function and associated morbidity. At least 146 mutations have now been described, 50 of which are newly reported here. The mutations, which occur along the length of the AGXT gene, are predominantly single-nucleotide substitutions (75%), 73 are missense, 19 nonsense, and 18 splice mutations; but 36 major and minor deletions and insertions are also included. There is little association of mutation with ethnicity, the most obvious exception being the p.Ile244Thr mutation, which appears to have North African/Spanish origins. A common, polymorphic variant encoding leucine at codon 11, the so-called minor allele, has significantly lower catalytic activity in vitro, and has a higher frequency in PH1 compared to the rest of the population. This polymorphism influences enzyme targeting in the presence of the most common Gly170Arg mutation and potentiates the effect of several other pathological sequence variants. This review discusses the spectrum of AGXT mutations and polymorphisms, their clinical significance, and their diagnostic relevance.


Available from: Antonio Amoroso, Jun 12, 2015
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    ABSTRACT: Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening.
    01/2015; 2015:634175. DOI:10.1155/2015/634175
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    ABSTRACT: Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.
    05/2015; 4(2):235-44. DOI:10.5527/wjn.v4.i2.235
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    ABSTRACT: Primary hyperoxaluria type 1 displays a heterogeneous phenotype, likely to be affected by genetic and non-genetic factors, including timeliness of diagnosis and quality of care. As previous genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of primary hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.Kidney International advance online publication, 2 July 2014; doi:10.1038/ki.2014.222.
    Kidney International 07/2014; DOI:10.1038/ki.2014.222 · 8.52 Impact Factor