Propionic Acidemia

Propionic acidemia can be a devastating condition; but with careful treatment, it is sometimes possible to reach adulthood successfully and even have babies.

Dr. Greene’s Answer:

Propionic acidemia (PA) can be a devastating condition; but with careful treatment, it is sometimes possible for people with the disease not only to reach adulthood successfully but even to get pregnant and deliver healthy babies!

But for parents whose children have PA, the first weeks after the symptoms appear seem like a surreal nightmare. Rather than little bundles of joy, or fussy bundles of colic, these children are floppy, weak, and fail to gain weight. Most often the children get increasingly lethargic and don’t have those wonderful, quiet, alert moments where baby and parent can connect. These symptoms generally begin to appear within the first couple of days of life. Up to 30% of infants may suffer from seizures, and almost all suffer from poor growth and dehydration. Most often the diagnosis is made within a few weeks of birth.  The diagnosis is important because, without quick interventions,  the situation can deteriorate, leading to seizures, heart arrhythmias, coma, and death.

Inborn Error of Metabolism

PA is what we call an inborn error of metabolism. Our bodies use detailed blueprints (our genes) to guide the manufacture of the proteins and enzymes we need to carry out the processes of life. Errors in these genes can lead either to a lack of necessary proteins or to the accumulation of toxic substances.

Most mutations in these genes cause no problem; they are just differences that set individuals apart. But more than 100 known single-gene changes do produce disease. Each of these inborn errors of metabolism is rare, but taken as a group, the conditions are fairly common. They range from very mild to quite severe. Even some of the worst can be successfully treated with something as simple as a dietary change. Others are relentlessly fatal.

Some of my most heart-rending experiences as a physician and as a friend have been watching the devastation caused by inborn errors of metabolism.

Inborn errors of metabolism should be suspected (and often aren’t) in any child with persistent vomiting, failure to thrive, lethargy, abnormal muscle function or tone, unexplained seizures, neurological deterioration, or developmental regression-especially in the absence of obvious congenital anomalies. A family history of a similar condition, a peculiar odor, or physical changes such as a large liver or spleen should also lead one to consider inborn errors.

Propionic Acidemia: An Error in Protein Metabolism

Every time we eat food that contains protein, our bodies use a series of enzymes to break those huge foreign protein molecules into small pieces. These then become the building blocks we reassemble to form the specific human proteins we need.

In people with PA, there is an insufficient supply of one of these enzymes (propionyl coenzyme A [CoA] carboxylase), caused by a mutation or abnormal changes in the PCCA and PCCB genes. There are over 70 different mutations that may cause the disease, and the severity of symptoms are based on how much working enzyme there is. Without the propionyl CoA carboxylase enzyme, there is a bottleneck in protein processing. Propionic acid builds up in the blood. This is known to damage the lining of small blood vessels, allowing the propionic acid to leak into the brain and nerve tissues, where it alters behavior and development. Ammonia also accumulates in the blood. This too can damage the brain. Food that is meant to nourish becomes a poison.

Propionic Acidemia is inherited in an autosomal recessive fashion, meaning affected persons carry one abnormal gene from each parent.  If you were to inherit one functional and one abnormal gene, you would be a carrier for the disease and likely not show symptoms. The risk of two carrier parents to have an affected child is 25% for each pregnancy.  PA affects males and females equally. The prevalence is about 1 in 100,000 to 200,000 in most regions of the world.  It is highest in the Greenlandic Inuit population; the rate there is thought to be about 1 in 1000.  

More Than One Form of Propionic Acidemia

There are two recognized forms of PA: a more severe infantile form and a milder (often) late-onset form. Babies with the neonatal form present with poor feeding and growth, low tone, weakness, vomiting, and seizures. The late-onset form presents in older childhood or young adulthood with chronic vomiting, developmental regression, weakness, protein intolerance, and occasional heart and movement problems.  Oftentimes these individuals come to the doctor for a heart or neurologic problem, and it is only after a long work up that an abnormal metabolic process is diagnosed.  The late-onset phenotype tends to be milder than the neonatal one.  However, in both forms of PA there can be multi-organ damage and long term devastating consequences to every organ system if not well treated.  

In either form of disease, acute attacks happen when the levels of protein to be digested are out of balance with the amount of enzyme available. In many individuals, there can be times of normalcy followed by acute attacks. Attacks might be caused by a high-protein diet, increasing the protein to be digested, or by stress or illness, decreasing enzyme production. Constipation can also trigger an attack because it increases dietary protein available for processing, and gut bacteria can produce additional propionic acid. These attacks can cause a rapid downward spiral in a child’s condition because the vomiting child with poor appetite, desperate for calories, will begin to process his own protein for food, leading to increasing levels of acid.

Laboratory findings during the acute attack reveal excess acid in the blood, low white blood cells (neutropenia), low platelets, and low blood sugar. Ammonia also accumulates in the blood. The level of ammonia often correlates with the severity of the disease, so this is measured to design and monitor treatment.

Treatment of Propionic Acidemia

Treatment of acute attacks includes rehydration, correction of acid-base balance, and provision of adequate calories, often through intravenous feedings. Minimal amounts of protein should be given, and this protein should be deficient in the four amino acids that need propionyl CoA carboxylase to digest them (isoleucine, valine, threonine, and methionine). To control the possible production of propionic acid by intestinal bacteria, antibiotic therapy (such as with metronidazole) should be started promptly. Constipation and other triggers need to be carefully monitored and treated. Patients with PA may develop carnitine deficiency, presumably as a result of urinary loss of propionyl carnitine. Administration of L-carnitine may be necessary to stop the attack.

Very ill patients with severe acidosis and elevated blood ammonia require dialysis to remove ammonia and other toxic compounds. Although infants with true PA are rarely responsive to biotin, this compound should be administered to infants during the initial attack. It is also very important in treating other errors of protein metabolism that look very similar.

Long-term treatment includes a low-protein diet. Synthetic proteins deficient in key amino acids (isoleucine, valine, threonine, and methionine) are used to increase the amount of dietary protein while causing minimal change in propionic acid production. Still, natural proteins should comprise most (50-75%) of the dietary protein.

L-carnitine supplementation is also a part of long-term treatment. And thiamin deficiency has been shown to make PA worse. Early vitamin supplementation is a good idea for these children, and especially when having an attack.

Close monitoring of blood pH, amino acids, urinary content of propionate and its metabolites, and growth curves is necessary to adjust the proper balance of the diet and ensure the success of therapy. Some patients may require chronic alkaline therapy to correct low-grade chronic acidosis. Also, children with PA are especially prone to infections. Any infection should be treated promptly.

Liver transplantation is a potential treatment for some patients with severe disease and frequent attacks. However, this does necessitate lifelong immunosuppressive medication to prevent the transplanted liver from being rejected. 

All patients with PA need to be followed closely by their team of doctors, as well as a nutritionist who is well versed in metabolic diseases.  With this type of regimen, some children do quite well, but treatment must be continued for a lifetime with conventional therapy.  It is also a good idea to involve a geneticist as part of the medical care team, as they can counsel carriers and affected individuals regarding the likelihood of passing on the disease to subsequent generations. 

Long-term Outcome for Propionic Acidemia

Long-term prognosis is guarded-especially in those who develop symptoms in the first week of life. Seizures occur in about 30% of affected infants. Survival has been improving dramatically in recent years, but death may still occur during an acute attack. This observed decrease in mortality is likely due to a combination of factors, including earlier diagnosis (due to newborn screening programs), better treatment, and elective liver transplantation. Normal development is possible, but most children do have some degree of permanent developmental deficit.

Strictly following a diet tailored to the child tends to improve results. But even apart from diet, outcomes vary considerably. In one family, a brother was diagnosed at 5 years of age, whereas his 13-year-old sister, with the same level of enzyme deficiency, had no symptoms at all!

The great news is that truly curing this disease, not just treating it, may be around the corner! Gene therapy is one method scientists have explored. In gene therapy, a missing or non-functioning gene is replaced by a new, functioning gene. In the laboratory, gene therapy for PA shows future promise for increasing lifespan. . However, it is not yet an approved treatment for PA in humans.  Successful gene therapy will not reverse brain or nerve damage, but can stop any further damage from occurring, giving the child a chance to grow unfettered. Coupled with important advances in early diagnosis, possible now even before a baby is born, the potential is huge.

As modern technology opens up new doors for a potential cure, one thing we do know about PA is that the earlier the disease is detected and treated, the better. I am absolutely thrilled by the recent action of so many states to screen all newborn babies for propionic acidemia and other genetic diseases. Baby’s First Test is a website that helps you to see what your state screens for in the newborn screen.  All states screen for a variety of metabolic disorders but not all states screen for the same ones.  I would encourage every family to seek newborn screening if at all possible. Early detection and action can make a major difference in children with PA and other inborn errors of metabolism.

Note: One good place to look to learn about ongoing clinical trials is clinicaltrials.gov.

This is NIH’s one-stop shopping area for information about clinical trials. Here you can access several databases containing facts about both public and privately supported clinical studies. Some of these studies are open to new participants, while others have already completed enrollment.

References and Resources

Barshes NR, et al.  Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatric Transplant. 2006;10:773–81.

Heringer J, et al. Impact of age at onset and newborn screening on outcome in organic acidurias. J Inherit Metab Dis. 2016; 39(3): 341-353.

Pena L, et al. Natural history of propionic acidemia. Mol Genet Metab. 2012; 105(1): 5-9.

Genetic and Rare Diseases Information Center

Propionic Acidemia Foundation

CDC Newborn Screen Information

Photo credit: Kristopher Strach

Dr. Greene is a practicing physician, author, national and international TEDx speaker, and global health advocate. He is a graduate of Princeton University and University of California San Francisco.

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  1. Jill

    Hi,

    The original question to Dr. Greene was posed by a friend of ours (Alli) after my son was diagnosed in 2000. A lot has happened since then.

    You can read stories about individuals with PA on our family stories page: http://www.pafoundation.com/family-stories/

    Jill

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  2. Alison

    I just turned 40 this october and i’ve been living with propionic acidemia since birth. I live in memphis, tn. I have a job, drive a car and do all the normal things people do. Have never been in the hospital for any problems. I have to drink a formula milk and take pills but thats it.

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    • Haris

      Hi,

      Glad to hear that you are fighting out this horrible problem like a true soldier. Can you please let me know about your daily diet in detail?

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      • Alison

        Before I answer. Who are you and do you have this condition and if so how old are you
        Sent from my iPhone

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        • Haris

          Fortunately I don’t have this problem but unfortunately my newborn son has this condition. He is month old now and having special formula diet. But down the road i was worried how we will be handling his food needs.

          That is why I was wondering how normal a food intake is for a grown person with this condition.

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          • Alison

            I take a special formula called propimex 2., isoleucine and valine, and carnitine. For me I am more of a vegetarian. I’ll ask my mom how she handled what I eat when I was little.

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      • Alison

        How bad is his condition?

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        • Haris

          Hi Alison

          Sorry for the late reply. My son was diagnosed quite early, actually on third day after his birth. So we are hopeful that his condition is not that bad. He has been since then on medication and special formula mixture with calculated quantity of protein in it.

          In your last reply you mentioned you are more of a vegetarian does that mean you don’t eat meat / chicken at all or you do have some small portions of it in you regular diet?

          And has your protein tolerance increased over the years as you have grown up?

          There are many things which are not clear to us and any guidance or information is invaluable to us.

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          • Alison

            My diet is a low protein diet. I eat some meat like bacon, hotdogs, hamburgers. The hamburgers not often. I don’t eat steak but if that’s the only think then I eat a small piece. My mom fed me food like wild rice, corn and sliced carrots from a can. I still eat that but now I eat pasta a lot. The. Formula I take I have to mix it up with cool aid to get take away from the taste and I’ll drink that with water or some kind of sandwich. Or break it down and take half in the morning and the other half at night.

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          • Alison

            So I talked to my mom and she said before they knew I had this condition she was feeding me sugar water and then they found about the condition when I was 6 months old. I don’t eat a lot of protein. I eat more carbohydrates and fats. But I now that I’m older I can have some protein but it has to be a small piece like a small steak but that’s only if someone is just cooking. I’ve tried different things to eat. But I’m still learning.
            Sent from my iPhone

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  3. Christina

    hi there. I’m 32 ,live in Australia , Greek and have had propionic acidaemia since birth. knowing that there are people out there that can live this long and longer is amazing and inspirational. hopefully a cure comes soon. but docs say I’ve done really well for a person with P.A. so keep at it people.

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    • Mariann

      My granddaugter 17 days old today (in Sweden ) has got propionic acidemia. In swedish propionsyrauri.

      What should I do?
      How am I going to think? I will think positive but it`s hard.
      She is so sick…

      Can you give me some tip how to think about the whole situation?

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  4. Chloé

    29 from the uk with propionic acidemia. To my knowledge I’m the oldest in the uk x

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  5. Deshae Griffin

    The oldest living person was 41 and he just was laid to rest today. Brent Burkett is his name. He was a joy. His was not discover until he was 18 months old and almost died.

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  6. Jarrod B.

    Dear
    Dr. Greene,
    Good early morning To You, my Name Is Jarrod From North Carolina. I Am A So-far Fighter Of Propionic Acidemia. I Was Diagnosed At The Age Of 2, back Then Not Much could Be Found Of this Disability. I Spent 3 weeks In a Coma And almost Died Once. But Anyways, dr. Told My Parents To Not Expect Me To Do Well In School Or Even Graduate High School. It Was A Hard Time But I Spent My Childhood Going In-n-out Of Hospital Not Able To Hold Food Down. I Stopped Taking My L-carnitine Medicine At The age Of 13. And only Go To Hospital once Every Few Years. It Has Been A Hard life, being Small Since I Couldnt Build Muscles Like Those Wrestlers I Watched On Television As a Child, i Still Have A Hard Time Reading Out Loud And i Havent Taken My Carnitine For Over A Decade Now. Ive gotten Kidney Stones Before, and I Have A Hard Time Holding A Normal Job but So Far thank Heavens the Tough Beginning Of childhood Tells Me To tell Others With This Disease Is “Miracles Do Happen” and I Hope To Be an Inspiration To Others. It Is Great Of This News Of A Cure For Future Generations To Come. I hope To Someday Find Out How I Am Surviving With This disability And Can I Help Others Like Me? So Families I pray You Find Hope In This Knowing Now feb. 9 2015 is A Living 28 Yr Old With This Disability. May You Be blessed

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    • sue

      My grandson is 4. It’s very inspirational knowing that you are 28 and going strong. You are a true blessing. Hopefully a cure will come soon.

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    • Mayda

      God bless you and give you more years to live. My daughter have GA type 1. She is almost 10 months old, but I have hope she will grow and be a healthy girl and live so many years.

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    • Bilal hussain

      Hi

      Both my nephews have this disease. My elder nephew (10 years) got diagnosed at around 8-9 months and was brain damaged badly in the process of finding out. Luckily my younger nephew (6 years) was diagnosed straight away when born. Now my wife is due to give birth to our third child who has 25% chances of this condition and me and my wife are carriers of this disorder.

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      • Sana

        Hi Bilal,

        Similar cases from around the world do help to combat one’s pain…hope your child will be well and devoid of PA..my niece has been diagnosed with PA..when she was 3 days old..though she is stable..doctors can’t comment exactly on future..so far so good..just wanted to know how is your younger nephew doing who was also diagnosed early..hope Allah cures all our children..

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    • Ali

      Hi my brother is 7 and he suffers from proponic acidemia we are from (uk) th doctors say theres not much they can do to help him get better. I wsd wondering if you had the liver transplant?

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      • Adeel

        Hi Ali. I am from the UK (Oldham, Greater Manchester) My daughter is 10 months old and has propionic acedmia. She was diagnosed at 3 weeks after having high ammonia. It would be great to get in touch

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      • Chloé

        Depending on the severity there is help out there (in the uk) I’m 28 with the condition. Had to fight for my doctor to get me help after years of problems. Found one of the best doctors that knows his stuff x

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        • Sana

          Hi Chloe,

          It would be helpful if you could let me know the doc details, my niece in UK has been diagnosed with PA..when she was 3 days old..yours is truly an inspirationalternative story..thanks for sharing..take care.

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        • Vongai

          Hi Chloe , this is really inspirational… My daughter who is now nearly 4 was diagnosed at day 3. We have been in and out of hospital especially first two years… She is now much stable but had has global developmental delay… could you please share details of your specialist, we are also in the U.K. … she is under Great Ormandy Street Hospital …

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