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About Primary Hyperoxaluria


Primary hyperoxaluria (PH) is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. In patients with PH, the kidneys are unable to eliminate the large amount of oxalate that is produced, and the accumulation of oxalate can result in severe damage to the kidneys and other organs. Currently, there are no approved therapies for the treatment of PH.

Learn more about PH, the unmet need for a treatment option, and Dicerna’s DCR-PHXC development program

 

What causes PH?

There are three known genetic forms of PH, each of which results from a mutation in a specific gene. The mutation causes a decrease in the activity of a specific enzyme in the liver, triggering an increase in oxalate production. In each case the decreased enzyme activity changes how the liver makes oxalate, resulting in overproduction of oxalate. The three forms of PH are: 1,2

  • PH1, caused by a mutation in the AGXT gene, which leads to a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT)
  • PH2, caused by a mutation in the GRHPR gene, which results in a deficiency of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR)
  • PH3, caused by a mutation in the HOGA1 gene, which causes a deficiency of the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA)

In some patients with PH, a genetic mutation has not been identified. These individuals are often referred to as having idiopathic PH (IPH) or “no mutation detected” (NMD) PH.

People with severe PH sometimes must undergo both liver and kidney transplants, which are major surgical procedures, and patients subsequently must take immunosuppressant drugs for the rest of their lives. Individuals with decreased renal function may also experience oxalosis, which involves a build-up of oxalate in other organs such as the bone, skin, heart, and retina, possibly causing other concomitant, debilitating complications.

 

How many people are affected by PH?

PH occurs in an estimated 1 in 120,000 live births around the world.1 The estimated genetic prevalence of PH1 is 1 in 151,887 births, which implies more than 5,000 patients in the United States and European Union have the disease.1 The estimated genetic prevalence of PH2 is 1 in 310,055 and that of PH3 is 1 in 135,866.1 The median age at the first appearance of PH1 symptoms is 5.8 years.2 The median age at diagnosis of PH1 is between 4.2 and 11.5 years, depending on whether nephrocalcinosis (calcification in the renal parenchyma, the functional part of the kidney) is present.3 Fifty percent of patients with PH1 reach end-stage renal disease  by their mid-30s.4

 

References

  1. Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.
  2. van der Hoeven SM, van Woerden CS, Groothoff JW. Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. Nephrology, Dialysis, Transplantation 2012; 27(10):3855-3862.
  3. Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney International 2015; 87:623-631.
  4. Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed July 6, 2017.