Propionic Acidemia

Propionic Acidemia
Q:
Propionic Acidemia

Some friends of mine recently had a baby who was diagnosed with Propionic Acidemia. Apparently this means that the baby cannot digest protein. The parents have talked with the doctors extensively about what they can do to help at home, life expectancy, etc., but they are consistently told that all cases are different and there’s no way to know what to do. Apparently it comes from a mutated (or recessive maybe?) gene that has to exist in both parents for the disease to appear in the child. I don’t think children with this disease live very long, nor do they develop mentally like healthy children. I think the oldest living person with the disease is 18. Any help you might provide would be greatly appreciated.Thanks in advance for your time.
Alli – Stockton, California

A:

Dr. Greene’s Answer:

Propionic acidemia 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 propionic acidemia, 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 and weak. Most often the children get increasingly lethargic and don’t have those wonderful, quiet, alert moments where baby and parent can connect. Not even feeding is a comfort, with vomiting and poor growth being common features. Often no one knows what the problem is, but without quick intervention, the situation can deteriorate quickly to seizures, coma, and death.

And when the diagnosis is finally made, the situation can sound even more bleak than the previous fears of the unknown. A nightmare indeed!

But a new treatment on the horizon may turn out to be a dream come true.

Propionic acidemia 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 is 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 propionic acidemia, there is an insufficient supply of one of these enzymes (propionyl coenzyme A [CoA] carboxylase). Without the propionyl CoA carboxylase, 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 really more than one disease, depending on the extent of the enzyme deficiency. In some people, the defect is complete, with the early onset of severe symptoms. At the other end of the spectrum, one man had such a mild deficiency that he didn’t develop symptoms until he was 31 years old!

There are now approximately 100 known different mutations to the propionic carboxylase gene (Mol Genet Metab. 2004 83:28). As our understanding of genetics accelerates, I expect that soon we will be able to make precise correlations between the specific genetic defect and the expected clinical course. Even now, though, we can tailor treatments to individual children while recognizing principles that apply to most children.

In general, those with intermediate levels of enzyme deficiency have symptoms that come in separate attacks when levels of protein to be digested are out of balance with the amount of enzyme available. This might be caused by a high-protein diet’s 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 because 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 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 should also be treated. Patients with propionic acidemia may develop carnitine deficiency, presumably as a result of urinary loss of propionylcarnitine. 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 propionic acidemia are rarely responsive to biotin, this compound should be administered to infants during the initial attack. It is very important in treating other errors of protein metabolism that look very similar.

Long-term treatment includes a low-protein diet (1.0-1.5 g/kg/24 hr). Synthetic proteins deficient in key amino acids (isoleucine, valine, threonine, and methionine) are used to increase the amount of dietary protein (to 1.5-2.0 g/kg/24 hr) while causing minimal change in propionic acid production. Still, natural proteins should comprise most (50-75%) of the dietary protein.

L-carnitine supplementation (50-100 mg/kg/24 hr orally) is also a part of long-term treatment. And thiamin deficiency has been shown to make propionic acidemia worse. Early vitamin supplementation is a good idea for these children-and especially when having an attack.

We used to think that the mental and developmental problems were solely a result of damage done during attacks. Recent evidence, however, suggests that damage may also occur even in the absence of attacks. Head MRI (which shows brain structure) and PET scan (which shows brain function) can be useful for following any silent progression of the disease.

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 propionic acidemia are especially prone to infections. Any infection should be treated promptly.

With this type of regimen, some children do quite well, but treatment must be continued for a lifetime with conventional therapy. In two known cases, the parents believed their children to be cured. They abandoned cumbersome diet and medications, resulting in the sudden death of both children.

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. 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 nonfunctioning gene is replaced by a new, functioning gene. In the laboratory, gene therapy for propionic acidemia has already worked (Am J Hum Genet Oct 2007). The hope is bright that within a few years the defect may be curable 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.

Auxiliary liver transplant is another strategy that has been explored for the treatment of inborn errors of metabolism. Affected children are essentially given an extra liver! The donated liver supplies enough of the missing protein to restore normal metabolism. Such transplants in children with propionic acidemia have been so successful that, in some cases, a protein-restricted diet was no longer needed.

As modern technology opens up new doors for a potential cure, one thing we do know about propionic acidemia 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 proprionic acidemia and other genetic diseases.

The National Newborn Screening and Genetics Resource Center keeps an updated list of states and the genetic conditions they routinely look for in their newborn screen. This information can be found at http://genes-r-us.uthscsa.edu/index.htm under the link labeled “Conditions screened by US programs.” In states where expanded newborn screening is not offered, parents can still have their babies tested by asking their doctors about testing through a private laboratory. 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 propionic acidemia and other inborn errors of metabolism.

Note: One good place to look to learn about ongoing clinical trials is http://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.

Reviewed by: Khanh-Van Le-Bucklin, Raanan Odom
Last reviewed: March 09, 2008
Dr. Alan Greene

Article written by

Dr. Greene is the founder of DrGreene.com (cited by the AMA as “the pioneer physician Web site”), a practicing pediatrician, father of four, & author of Raising Baby Green & Feeding Baby Green. He appears frequently in the media including such venues as the The New York Times, the TODAY Show, Good Morning America, & the Dr. Oz Show.

 

Comments