Genotype–phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome

Abstract

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

Characteristics and Outcomes of Children with Primary Oxalosis Requiring Renal Replacement Therapy

“…Although we found no association of dialysis duration on patient or kidney graft survival, unlike in other studies (7,14), the increasing time spent on dialysis by PH children may jeopardize some of the progress seen in this study. This time may reflect the younger age of the population as well as the longer waiting time for combined liver-kidney transplantation.…”

“…Patients with PH1 may benefit from conservative treatment measures, including aggressive hydration, calcium oxalate crystallization inhibitors, and pyridoxine (4,5), but usually progress to ESRD over time at a median age of 24-35 years (6)(7)(8). Children who are symptomatic during infancy have a more severe course and most of them reach ESRD before the age of 3 years (9).…”

Primary Hyperoxaluria: A Sri Lankan Case Series

“…The median age at end-stage renal disease was 47 years in pGly170Arg homozygote and 35 years in heterozygote. Among patients with other mutations, the median age at endstage renal disease was 21 years [3]. Primary hyperoxaluria type 2 less common than type 1, and the defective enzyme is D-glyceric dehydrogenase.…”

“…Primary hyperoxaluria type 1 has variable presentation; an infantile form; recurrent urolithiasis and progressive renal failure in childhood or adolescence; and late-onset form with occasional stone passage, and end stage renal disease [3]. Symptoms of primary hyperoxaluria type 2 occurs late in childhood, form less calculi, have a less pronounced nephrocalcinosis, and a lower incidence of end stage renal disease over time, compared to primary hyperoxaluria type 1 [3]. Interestingly, in our case series patients have developed end stage only in their early third decade.…”

“…Systemic oxalosis is thought to take place once the GFR falls below 30-50ml/min [3]. First patient showed extensive bone involvement due to oxalosis (Figure 1 & 2), which resulted in severe bone pain and radiological changes.…”