Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias

Rumsby, Gill; Williams, Emma; Coulter‐Mackie, Marion B.

doi:10.1111/j.1523-1755.2004.00842.x

Cited by 92 publications

(55 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Minor and major allele frequencies were 57 and 43%, respectively. The c.33_34insC frameshift mutation was the second most common change after G170R, with an allelic frequency comparable to what has been reported in larger populations (11%) [8]. …”

Section: Resultssupporting

confidence: 50%

“…The AGT peroxisome-to-mitochondria mistargeting phenotype appears to functionally separate the enzyme from its substrate, glyoxylate, even though enzyme activity of up to 70% of normal has been documented in some G170R homozygotes [8]. Indeed, our data seems to indicate that residual AGT catalytic activity is proportional to the number of G170R alleles, being highest in the G170R homozygotes (table 1), albeit cohort size is small.…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Implications of Genotype and Enzyme Phenotype in Pyridoxine Response of Patients with Type I Primary Hyperoxaluria

2005

View full text Add to dashboard Cite

Background: Marked hyperoxaluria due to liver-specific deficiency of alanine:glyoxylate aminotransferase activity (AGT) characterizes type I primary hyperoxaluria (PHI). Approximately half of PHI patients experience improvement in the degree of hyperoxaluria following pyridoxine (VB6) treatment. Recently, we showed an association between VB6 response and the commonest PHI mutation G170R, with patients possessing one or two copies showing 50% reduction or complete to near complete normalization of oxaluria, respectively. Two patients showed responses varying from this pattern. To further clarify the molecular basis of VB6 response in PHI, we performed additional genotyping. Methods: 23 PHI patients diagnosed via hepatic enzyme analysis, hyperoxaluria and hyperglycolic aciduria or homozygosity for a known mutation, availability of pre- and post-VB6 24-hour urine oxalate and GFR >40 ml/min/1.73 m² were included. Data was retrieved retrospectively, oxalate measured by oxalate oxidase, and genotyping performed by PCR-based methods. Results: VB6 response was associated with the G170R and F152I mutations. Eight new sequence changes were detected. Conclusions: In PHI, two mutations resulting in AGT mistargeting are associated with VB6 response. Whether this favorable effect is specific to the peroxisomal-to-mitochondrial mistargeting caused by these changes or due to another mechanism remains to be determined.

show abstract

Section: Resultssupporting

confidence: 50%

Section: Discussionmentioning

confidence: 75%

Implications of Genotype and Enzyme Phenotype in Pyridoxine Response of Patients with Type I Primary Hyperoxaluria

2005

View full text Add to dashboard Cite

show abstract

“…The 3 most common mutations of AGXT (c.508G>A, c.33_34insC, c.731T>C) together account for approximately 45% of mutant alleles in patients with PH I. Screening of these 3 mutations identified one or more of them in 69% of biopsy-proven cases of PH I in one recent series [48]. Thirty-four percent of the patients (179/287) were homozygous or compound heterozygous, making a molecular diagnosis possible.…”

Section: Algorithmmentioning

confidence: 99%

The Primary Hyperoxalurias: An Algorithm for Diagnosis

Milliner¹

2005

Am J Nephrol

View full text Add to dashboard Cite

Background/Aims: The primary hyperoxalurias (PHs) are inborn errors of metabolism resulting in increased urinary excretion of oxalate. Nephrolithiasis, nephrocalcinosis, and renal failure result. Renal failure can occur as early as infancy or as late as the sixth decade of life, and if not addressed promptly, results in severe morbidity and mortality related to systemic oxalate deposition (oxalosis). Clinicians are likely to encounter few PH patients during a practicing lifetime. Definitive diagnosis requires special studies performed in only a small number of laboratories worldwide. Accordingly, delays in diagnosis are common. Methods: An evidence-based guideline for diagnosis was developed. Results: Patients with stones or nephrocalcinosis in childhood, recurrent calcium oxalate stones in adulthood, or renal insufficiency associated with stones or nephrocalcinosis should be evaluated for PH. A systematic approach to measurement of urine oxalate, glycolate and glycerate, and plasma oxalate is provided. Age-related variation in urine oxalate requires attention to normal ranges. Molecular analysis for mutations of the AGXT gene (PH, type I) or GRHPR gene (PH, type II) is definitive in some patients, while liver enzyme analysis is required for confirmation of the diagnosis in the remainder. Conclusion: An evidence-based algorithm will facilitate recognition and diagnosis of patients with the PHs, permitting earlier treatment.

show abstract

“…Typical allele frequencies of these mutations are shown in table 1. Together these four account for more than 50% of PH1 alleles [15]. Different laboratories report slightly different allele frequencies depending on the population mix of the samples tested, but these four mutations form the basis of an initial mutation screen in the genetic diagnosis of PH1 [15].…”

Section: Introductionmentioning

confidence: 99%

Preliminary Evidence for Ethnic Differences in Primary Hyperoxaluria Type 1 Genotype

Coulter‐Mackie

2005

Am J Nephrol

View full text Add to dashboard Cite

Background: Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of peroxisomal alanine:glyoxylate aminotransferase (AGT). In about one third of patients, enzymatically active AGT is synthesized but is mistargeted to mitochondria. There are more than 50 mutations identified in the gene for AGT. Four mutations, G170R, 33_34insC, F152I and I244T account for more than 50% of PH1 alleles. The question arose whether there are ethnic differences in PH1 genotype. Methods: The published data on mutations in the AGT gene were examined with respect to recurrences and geographic or ethnic association. The mutations that have been found in at least 2 unrelated individuals were considered. Results: Two common mutations, G170R and 33_34insC showed no obvious ethnic associations and have been found in a variety of populations. A third common PH1 mutation, I244T, has a strong association with people from a Spanish or North African background. A particularly high frequency among Canary Islands PH1 patients suggests a probable founder effect. Between these two extremes are a number of mutations that recur at low frequency within certain ethnic groups. Conclusions: Ethnic associations of PH1 genotypes span a spectrum ranging from limited recurrences confined to a population group, to a probable founder effect.

show abstract

Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias

Cited by 92 publications

References 19 publications

Implications of Genotype and Enzyme Phenotype in Pyridoxine Response of Patients with Type I Primary Hyperoxaluria

Implications of Genotype and Enzyme Phenotype in Pyridoxine Response of Patients with Type I Primary Hyperoxaluria

The Primary Hyperoxalurias: An Algorithm for Diagnosis

Preliminary Evidence for Ethnic Differences in Primary Hyperoxaluria Type 1 Genotype

Contact Info

Product

Resources

About