Dr. Greene’s Answer:

Each meal is a matter of life and death for children with propionic acidemia. Children need protein in order to grow and thrive, but for these children extra protein is a deadly poison.

Here’s the problem: The amount they need to grow is a little more than the amount they can handle. Each meal becomes a delicate balancing act that can make the difference between normal development and long-term disability.

Knowing that your baby has this precarious illness must make the desire to nurse and comfort your baby even stronger. But, as cruel as it seems, even breastmilk can be dangerous, unless it is used in just the right way.

Propionic acidemia is one of what we call the inborn errors of metabolism. The individual metabolic disorders are rare, but taken as a group they are fairly common. I do know women who have nursed successfully with metabolic disorders. Some of the metabolic disorders make nursing difficult but still a great benefit.¹ Others make nursing harmful.²

Normally, when we eat protein in our food, our enzymes break the protein down into molecular building blocks. We then reassemble these into the specific protein molecules and other substances our bodies need. Proteins are made up of amino acids.

In propionic acidemia, one little enzyme is missing, but this is enough to change an entire life. Without the enzyme propionyl CoA carboxylase, some common amino acids in protein (isoleucine, valine, threonine, and methionine), are only partially processed. One of the intermediate stages, propionic acid, builds up in the bloodstream.

The propionic acid causes poor feeding, vomiting, dehydration, floppiness, and lethargy, which usually show up in the first weeks of life, and can progress rapidly to coma and death. Seizures occur in about 1/3 of babies. If a baby survives the first attack, similar episodes may occur during an unrelated infection, constipation, or following a high-protein meal.

Some children sail through the early months without apparent problem and don’t come to attention until much later in life.

Before it was recognized and treated, propionic acidemia was usually fatal. With right treatment, it is possible for children to grow and develop normally. The right treatment is crucial. It greatly improves children’s odds but is not the whole story.

Some children are treated perfectly and still have bad outcomes. Others receive no treatment at all and thrive. Even within the same family, there can be wide variability of this disease. One boy was first diagnosed at age 5 because of mental retardation; his 13-year-old sister turned out to have the same level of enzyme deficiency but had no symptoms at all!³

The cornerstone of treatment is to restrict protein. Other measures can be helpful (supplementing with L-carnitine, supplementing with thiamine,⁴ using antibiotics to kill gut bacteria that produce amino acids, using alkaline treatment to decrease acid, treating any constipation immediately, etc), but without restricting protein, none of the other treatments help.

Generally with the low-protein diet, regular protein must be restricted to 1.0-1.5 g/kg per 24 hours. To get enough protein to grow and thrive, kids can supplement this with specially made proteins without isoleucine, valine, methionine, and threonine. This allows the total protein to be increased to 1.5-2.0 g/kg per 24 hours.⁵ The baby needs to be carefully monitored, especially during times of stress or infection, to achieve just the right balance of protein.⁶

I was not aware of anyone who had breastfed successfully with propionic acidemia, so I contacted Iraj Rezani, M.D., the Chief of the Section of Metabolic Disorders at the Temple University Children’s Medical Center and the author of the leading pediatric text on propionic acidemia. He explained that the act of nursing is impossible, even once a day, because the concentration of protein in human milk (1.5%) is just too high-even in small amounts. In those few precious days after a baby is born and before a mom’s milk comes in, the concentration of protein is even higher in the little bit of colostrum that appears. Breastmilk must be pumped, diluted, and carefully measured to be safely used.

In the past few years, researchers at the Istanbul Medical Faculty in Istanbul, Turkey, have studied the possibility of safely breastfeeding children with inborn errors of metabolism. Unfortunately, to date, only one child with propionic acidemia was included in their studies. During three months of breastfeeding, that child had two metabolic emergencies and was quickly switched to a low-protein formula. (Journal of Inherited Metabolic Disease. 28(4):457-65, 2005.)

Ross Labs (with whom I have no affiliation) has designed a comprehensive line of medical foods designed to meet nutrition needs in people with this and other inborn errors of metabolism (more than 3 dozen in all). I applaud them for addressing the needs of families with these rare conditions. Propimex-1 is a ready-to-feed formula for infants and toddlers. Propimex-2 is designed for children and adults with propionic acidemia.

I am hopeful that, in your baby’s lifetime, gene therapy will be able to replace the missing enzyme. For now, liver transplantation is the most effective way to do this.⁷ But unless and until your child has the enzyme replaced, the propionic acidemia diet should be followed carefully.

I feel for the poignancy of your situation. Because your baby was diagnosed before birth, I suspect there may have been another baby in your family who died. How hard this time must be for you!

I am a huge fan of nursing, but I am also confident that the love you already feel will surround and caress and comfort and nourish your baby. When people are denied their eyesight, their other senses become more powerful. I observe that when people who want to nurse are denied the opportunity, all of the other ways of bonding give rise to unexpected levels of closeness.

Dr. Greene’s Answer:

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.

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.

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.

Dr. Greene’s Answer:

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.

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!

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.

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.

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.

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.

Dr. Greene’s Answer:

Galactosemia is a metabolic disease that can cause ovarian failure. Children with galactosemia are missing an enzyme needed to process a sugar called galactose. This is found in the diet primarily in lactose (in dairy products and many nutritional and pharmaceutical extenders). Galactose is now known to be present in many other foods, especially beans and peas. When you have galactosemia, the ovaries are slowly destroyed over the course of the first few decades of life (but not testicles, for unknown reasons). Although a strict galactose-free diet may be able to curtail a life-threatening metabolic derangement in newborns, continued avoidance of galactose does generally not prevent other long-term complications, including ovarian failure. The exact mechanism by which the inability to process galactose injures the ovaries is uncertain.

Widespread newborn screening for galactosemia in the United States has made undetected galactosemia uncommon. For those who have not been screened, a blood test or urine test can screen for the condition. Most people with galactosemia will develop obvious symptoms in infancy.

Dr. Greene’s Answer:

Six known categories of insults can destroy the ovaries of a young woman. Some of them are reversible; some of them are not.

One in 10,000 women between the ages of 15 and 29 years experience premature permanent ovarian failure. Menopause at only 17! What a blow for your daughter. Unless something changes, she will never leave descendants to carry her life forward through the generations. Her body will begin to age at a faster pace. Postmenopausal complications are accelerated (osteoporosis, heart disease, wrinkles, dryness, sagging breasts, diminished sex drive…).

Adolescence is a time for connecting with others. It is also a season of intense body image concerns. Going through menopause as a teen can leave a young woman feeling abnormal, isolated, and empty. And teens can’t yet perceive the full journey of life, so she can’t really know all that she is missing… But you, as her mom, know the depth of what she could miss throughout her life; you feel the loss. Perhaps she will never know the sweet ache of motherhood or the exalted joy of being a grandmother.

What could have destroyed her ovaries? Is this permanent? Can it be corrected? Let’s take a look at some possible causes.

Toxins

The damage from chemicals or radiation can devastate the ovaries. Most often this is a side effect of the treatment of a serious illness. This can be permanent — but not always. I recently read about a 14-year-old girl who needed intense chemotherapy for a nasty cancer. Her ovaries vanished, and lab tests confirmed that this would likely be permanent, which is why it took more than four months for her to think about getting a pregnancy test when she became pregnant at age 22! Her ovaries quietly began functioning again on their own.

Genetics

As many as 30% of teens with ovarian failure have an underlying chromosome problem. Turner syndrome is the most common problem, but many small defects in the X chromosome can cause ovarian failure — as can a number of rarer conditions. Any girl with vanishing ovaries must have a chromosome test and a FISH (fluorescent in situ hybridization) test to look for chromosome problems. Rarely, even a male Y chromosome is found in an otherwise normal girl.

Autoimmune Diseases

In several autoimmune diseases, a girl’s body can begin to make antibodies that attack the ovaries. This is most common in girls with Addison disease, diabetes, and various thyroid diseases, but can also occur in those with lupus, hypoparathyroidism, adrenal insufficiency, and a number of other autoimmune diseases. The more glands that are involved, the more likely it is that the ovaries will be affected by these antibodies. Young women with ovarian failure should be tested for autoimmune diseases. It is possible for medication to block the antibodies allowing ovarian function to return. Women in this situation have resumed their periods and become pregnant — as long as seven years after the ovaries were apparently destroyed!

Metabolic Conditions

The classic metabolic disease causing ovarian failure is called galactosemia. Children with galactosemia are missing an enzyme needed to process a sugar called galactose. This is found in the diet primarily as lactose (in dairy products and many nutritional and pharmaceutical extenders). Galactose is now known to be present in many other foods, especially beans and peas. When you have galactosemia, the byproducts of galactose can destroy ovaries (but not testicles, for unknown reasons). A strict galactose-free diet may be able to save the ovaries, especially in mild cases of galactosemia.

Widespread newborn screening for galactosemia in the United States has made undetected galactosemia uncommon. For those who have not been screened, a blood test or urine test can screen for the condition. Most people with galactosemia will develop obvious symptoms in infancy.

An iron storage disease called hemochromatosis can also cause ovaries to vanish. In this disease, if you remove excess iron and replace deficient pituitary hormones, the ovaries might be salvageable.

Hormonal Conditions

Ovarian size and function can diminish from a lack of the hormones needed to stimulate the ovary (gonadotropins). These are normally produced in the head — in the pituitary gland and the hypothalamus. Sometimes the problem is that the ovary is resistant to these necessary hormones, so that it can’t be stimulated.

Women with these conditions are diagnosed with blood tests, and sometimes respond to appropriate treatment.

Infectious Diseases

Mumps is the classic infection that can destroy ovaries. Thankfully, this disease can be prevented with the routine MMR (measles, mumps, rubella) vaccine.

What to Do?

Short-term priorities are to diagnose what is going on with your daughter, and to provide your family with whatever support you need in the process. I would start with a reproductive endocrinologist to get to the bottom of this mystery, if possible. Perhaps the condition can be corrected.

Long-term priorities will depend on what you find. If ovarian function can’t be restored, work with her reproductive endocrinologist to design a program of hormone replacement to combat many of the effects of ovarian failure. This can prevent osteoporosis and heart disease, and enhance vitality and sexuality. If, in the chromosome analysis, any Y chromosome is detected, surgery to remove any ovarian remnants is wise to prevent cancer. Your loving support is vital for your daughter. Support her in learning to see the miracle of who she is, just as she is.

Also support her in exploring reproductive options if she so desires. As reproductive science races forward, new possibilities are likely in the next few years. Some are already here: Even if her ovaries don’t function again, with her intact uterus she is likely to be able to carry a donated egg, and still discover the marvel of having a baby growing inside her. Even though the DNA would not be hers, the entire substance of the baby would be formed out of the “stuff” of her body. The blueprint might be borrowed, but the building would be hers. She could still experience the heights and depths of motherhood — the ocean of mother-love that you feel right now and the joy of making you a grandmother.