Course:MEDG550/Student Activities/Primary hyperoxaluria type 1

From UBC Wiki

Primary Hyperoxaluria Type 1 (PH1) is a genetic condition involving the kidneys. People with PH1 are missing an enzyme that controls the levels of a substance called oxalate in their bodies. The symptoms of PH1 happen when oxalate builds up, leading to the formation of kidney stones and other health concerns.

Signs and Symptoms

PH1 affects people differently. Symptoms range in severity and usually begin to develop in childhood, but can happen any time from shortly after birth up to middle-age.

People with PH1 may develop some or all of the following features:

  • Frequent kidney stones (recurrent nephrolithiasis)4: Kidney stones form when certain salts and minerals build up and stick together in the kidneys. People with kidney stones may feel pain in their belly and lower back, and experience a burning sensation when peeing and blood in the urine. Kidney stones may pass naturally through the urine, or may require a procedure to be removed.
  • Frequent urinary tract infections (recurrent UTIs)4: A UTI is an infection in any part of the urinary system—the kidneys, the bladder, the tubes that connect the kidneys to the bladder (ureters), and the tube that we pass urine through (urethra).
  • Calcium build up in the kidneys (nephrocalcinosis)4
  • Renal (kidney) failure4: Normally, the kidneys function to filter unwanted products from the blood which are then removed through the urine. When the kidneys are damaged they no longer work properly, meaning that they are unable to filter unwanted products from the blood as well as they should. This allows unwanted products to build up in the body. Kidney failure is progressive, meaning that it occurs gradually and becomes worse over time.
  • Oxalate build up in the body (oxalosis)4,7: Oxalate must be removed from the body through the urine. When oxalate levels become too high, the body cannot get rid of it fast enough and it collects in other parts of the body—first the blood, then the eyes, bones, muscles, and other organs.
  • End-stage renal disease (ESRD)4: ESRD is the last stage of kidney failure. At this point, the kidneys no longer work to filter blood on their own and dialysis or a kidney transplant is needed to stay alive.

Genetics

AGXT Gene

Processing of glyoxalate when AGT is not working properly

Humans are made up of billions of cells and inside of these cells are molecules of DNA. Genes are small segments of DNA that contain instructions for how to make proteins, which carry out important tasks in the body. Changes in the DNA sequence of a gene are like spelling mistakes that alter the set of instructions. Depending on the type of change, this may have an impact on the protein that is produced—it may not work as well as it should, work in the wrong location in the body, or not work at all.

PH1 is caused by changes, or "variants", in the AGXT gene, which produces a protein called alanine-glyoxylate aminotransferase (AGT)1. AGT is an enzyme, which is a type of protein that speeds up chemical reactions in the body. AGT can be thought of as a worker in a factory assembly line whose job it is to turn the molecule glyoxylate into glycine. When AGT is not doing its job properly, it results in the build up of glyoxylate. The body tries to get rid of this extra amount of molecule by turning it into oxalate, which can be "shipped out" from the body through the urine. Unfortunately, oxalate is a compound that is difficult for the body to get rid of—it does not dissolve easily and likes to stick to a mineral called calcium. The formation and buildup of calcium oxalate crystals (stones) in the kidneys causes the problems associated with PH16.

Autosomal recessive inheritance pattern

Inheritance Pattern

PH1 passes through a family in an autosomal recessive pattern5. Every individual has two copies of every gene in their bodies: one copy inherited from their mother and one copy inherited from their father. As an autosomal recessive disorder, both copies of the AGXT gene must not be working properly in order for a person to be affected by PH1. People who have one non-working copy of AGXT are referred to as "carriers". Carriers will not develop PH1 because they have one working copy to pick up the slack created by the copy of the gene that isn't working, but there is a 50% chance that they will pass on the non-working copy to any child that they have. When two carriers have a child together, there are three possibilities for their baby:

  • 25% chance that their child will inherit two working copies, one from both mother and one from father, and will be unaffected by PH1
  • 50% chance that their child will inherit one working copy and one non-working copy, meaning that they will be not be affected by PH1, but will be a carrier themselves
  • 25% that their child will inherit two non-working copies and will be affected by PH1

PH1 affects both men and women equally.

Diagnosis via Genetic Testing

A diagnosis of PH1 is confirmed by genetic testing of the AGXT gene4,8. This test examines the entire length of DNA instructions in the gene for changes that may prevent the gene from working as it should (full sequence analysis). More than 97% of harmful variants in AGXT are detected with full sequence analysis, but a few changes will be missed4. In this case, a small piece of the liver is removed (liver biopsy) and looked at for activity of the AGT enzyme.

Genetic Counselling

If a family member has PH1, it may be helpful to have genetic counselling in order to better understand what the implications are for you and your loved ones. Genetic counsellors are specially trained to help patients understand and adapt to genetic diagnoses. They can provide education and psychological support to parents who are navigating difficult decisions, and can facilitate the option of genetic testing so that individuals can better understand their chances of having a child with PH1.

Recurrence Risk

If a couple already has a child with PH1, this means that they are both carriers (one non-working AXGT gene) and there is a 25% chance of PH1 in every future pregnancy.

If a patient with PH1 has a child with a partner who is not a carrier, there is a very low chance that their baby will have PH1, but the child will be a carrier. If the partner of a PH1 patient is a carrier, their child will have a 50% chance of having PH1 and a 50% chance of being a carrier.

Testing Options

Carrier testing: If the specific change in the AGXT gene causing PH1 in a family is known, family members can be tested to see if they also have that change. If someone with PH1 is interested in having a baby, their partner can also have carrier testing by full sequence analysis to determine the chance of the couple having a pregnancy affected by PH1.

Prenatal testing: Testing a pregnancy to see if the baby has PH1 is possible for parents who are both carriers as they have a 25% chance of having an affected child. A genetic test that looks for known changes in the parents' AGXT gene which may be present in the baby can be performed through one of the following procedures:

  • Chorionic villus sampling (CVS): A sample of the placenta is taken through the belly or cervix at 11-13 weeks of pregnancy
  • Amniocentesis: A sample of the fluid surrounding the baby is taken by inserting a needle through the belly after 15 weeks of pregnancy

Prenatal genetic diagnosis (PGD): Couples who are carriers may choose to do in-vitro fertilization (IVF) and test each embryo individually. An embryo that is found not to be affected by PH1 will be used to start a pregnancy (implanted).

Psychosocial Considerations

PH1 is a condition that is life-threatening if not properly managed, and has a wide range of symptoms that can change a person's day-to-day life. It can be tough to predict how seriously someone with PH1 will be impacted—they may experience only small complications due to the disease, or may be very sick for their whole life. Some people pass away during childhood, whereas others live long lives and never progress to ESRD. Every person who comes into a genetic counselling appointment will have different experiences with PH1 and have a unique frame of reference. For parents, it is common to experience uncertainty and anxiety regarding what to expect for their child due to the broad range in severity and age of onset. Personal experience will inform understanding of the condition, which may be helpful to share with your health care provider in order to explore and talk through any difficult choices that may arise. PH1 is a rare condition, so finding a support system in your family or within the worldwide community may help to feel connected.

Management

The goal of PH1 management is to keep the kidneys healthy so that they can do their job. It is important to diagnose the condition early so that treatment can be started to prevent the disease from getting worse.

Prevention

There are lifestyle changes and medications that may help to limit the formation of kidney stones, including:

  • Drinking lots of fluids to maintain urine volume. This will help to prevent calcium oxalate from building up and forming stones4
  • Taking substances to stop stones from forming (oral potassium citrate, pyrophosphate, magnesium)5
  • Avoiding large amounts of vitamin C as it promotes stone formation5
  • Avoiding NSAIDS (aspirin, ibuprofen) or medications that may be hard on the kidneys4
  • Avoiding foods that are high in oxalate (chocolate, rhubarb)4
  • Taking vitamin B6 (pyridoxine) to make the AGXT enzyme work better. This therapy works in different ways depending on which change in the AGXT gene the person has2,3,5

Treatments

Treatment of PH1 is based on a managing a person's symptoms.

  • Removal of stones
    • Using sound waves to break up smaller stones (extracorporeal shock wave lithotripsy)4
    • Having a minor surgery to remove larger stones (percutaneous nephrolithotomy)4
    • Using a small tube with a camera on it to remove stones through the urinary tract (uteroscopy)4
  • Dialysis: Dialysis is a treatment that filters and cleans the blood using a machine. People with compromised kidney function may need dialysis to remove oxalate from the blood and keep the amount of oxalate at a safe level4.
  • Organ transplantation: An organ transplantation is a type of surgery that replaces a damaged organ with one that is healthy. When a person with PH1 has enough calcium oxalate buildup such that their organs are not working properly, they may need a new liver (liver transplant), new kidneys (kidney transplant), or both (liver-kidney transplant)4. A liver transplant is the only treatment that helps to overcome the disease and promote recovery (curative treatment).

Surveillance

People with PH1 should have their kidney function monitored regularly. The level of surveillance depends on how well the kidneys are working and is specific to the person. People with PH1 may need some or all of the following tests:

  • Blood test to see how well the kidneys are working (glomerular filtration rate)
  • Ultrasound of the kidneys (renal ultrasounds)
  • Examining the urine for appearance and composition (urinalysis)
  • Eye exams to check for oxalate build up (funduscopic eye examinations)
  • X-rays to check for oxalate build up in the bones of the arms and legs
  • Ultrasounds of the heart to check for oxalate build up (echocardiograms)

Patient Resources

To locate a genetics clinic near you, speak to your health care provider or visit www.cagc-accg.ca (Canada) or www.nsgc.org (United States).

References

  1. AGXT gene. https://ghr.nlm.nih.gov/gene/AGXT#conditions
  2. Fargue S, Rumsby G, Danpure CJ. Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1. Biochimica et Biophysica Acta 1832 (2013): 1776-1783.
  3. Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC. Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. JASN Oct 2015, 26 (10) 2559-2570.
  4. Milliner DS, Harris PC, Cogal AG, et al. Primary Hyperoxaluria Type 1. 2002 Jun 19 [Updated 2017 Nov 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
  5. Primary hyperoxaluria type 1. https://rarediseases.info.nih.gov/diseases/2835/primary-hyperoxaluria-type-1
  6. Primary Hyperoxaluria. https://ghr.nlm.nih.gov/condition/primary-hyperoxaluria
  7. Oxalosis. https://www.physio-pedia.com/Oxalosis#:~:text=Oxalosis%20is%20a%20rare%20metabolic,from%20the%20body%20through%20urine.
  8. Abukhatwah MW, Almalki SH, Althobaiti MS, Alharbi AO, Almalki NK, Kamal NM. Primary hyperoxaluria Type 1: A case report in an extended family with a novel AGXT gene mutation. Medicine (Baltimore). 2020;99(25):e20371. doi:10.1097/MD.0000000000020371